Key Points:
- A need for various lipid-lowering agents to combat high cholesterol exists for those already taking statin medications.
- Vupanorsen is a monoclonal antibody that inhibits lipoprotein lipase and has been shown to decrease non-HDL cholesterol in phase II trias.
- In this phase III trial, vupanorsen was found to reduce non-HDL cholesterol by up to 28% in patients who were already taking a statin medication, however was associated with injection site reactions and elevated liver enzymes at higher doses.
Non high-density lipoproteins (non-HDLs) are associated with elevated risk of cardiovascular disease and myocardial infarction. While statin medications lower this risk, a need remains for adjunctive therapies in patients whose risk remain elevated. Vupanorsen is a drug that targets Angioprotein-like protein 3 (ANGPTL3), the protein that inhibits lipases, included lipoprotein lipase. Patients with a loss of function variant of ANGPTL3 had lower levels of plasma lipids, and thus the concept of this monoclonal antibody was conceived. In the phase II trial of the drug, vupanorsen was found to decrease ANGPTL-3 by 62%, achieving a 44% reduction in triglyceride levels and an 18% reduction in non-HDL cholesterol. To determine whether greater reduction in cholesterol could be achieved, the phase III TRANSLATE TIMI 70 trial was conducted, assessing the effects of various doses of vupanorsen on non-HDL cholesterol over 24 weeks.
In a late breaking clinical trial session at the 71st annual American College of Cardiology Scientific Sessions today, Dr. Brian Bergmark (Brigham and Women’s Hospital, Boston, MA) revealed the results of TRANSLATE-TIMI 70. In this multinational, randomized-control trial, participants with elevated non-HDL-levels who were already tolerating a statin medication were randomized to receive vupanorsen at various doses and time periods, ranging from 60mg every 2 weeks to 160 mg every 2 weeks. Lipid testing was performed at baseline and at the conclusion of the study.
The 286 participants were mostly male (56%) with an average age of 64 years. Half of the participants had Type 2 Diabetes and all were on a statin, the majority of which were high intensity statins. At 24 weeks, all dosing regimens of vupanorsen were associated with significant reductions in non-HDL-C and triglyceride levels. When the highest dose of 160mg every 2 weeks was administered, ANGPTL3 was reduced by 95%, and triglycerides by 56.8%. The effect was more pronounced in women, those without diabetes, and those older than 65 years of age.
The drug appeared to be well tolerated at lower doses, but higher dosing frequency was associated with not only injection site reactions, but elevations in liver enzymes as well. Overall, the authors concluded that the drug is effective, but further, higher-powered studies are required to evaluate the optimal dose, and to better understand the mechanism of adverse reactions.
The study was published simultaneously in Circulation.