Vupanorsen Falls Short Despite HDL-C Reduction in TRANSLATE-TIMI 70

Antisense oligonucleotide ANGTYL3 inhibitor vupanorsen provided significant reduction of non-high-density lipoprotein cholesterol (HDL-C) in adults with hyperlipidemia at 24 weeks.

The late-breaking data from the TRANSLATE-TIMI 70 trial presented at the American College of Cardiology (ACC) Scientific Sessions in Washington, DC, this weekend showed the investigative monthly injection therapy may provide clinicians a novel mean of lowering patients’ lipids.

However, investigators additionally found the hepatic-targeting vupanorsen was associated with significant elevations in patients’ liver enzymes—a risk that investigators believe may exceed the benefit of lipid-lowering capability seen with the drug.

In an interview with HCPLive during ACC 2022, study author Brian A. Bergmark, MD, associate physician of interventional cardiology at Brigham and Women’s Hospital, described vupanorsen’s “fairly modest” impact on other hyperlipidemia markers LDL-C and apolipoprotein B (ApoB). Coupled with the unanticipated safety outcomes, future assessment of the once-promising agent will possibly need to come from a different indicated use.

“Personally, I think these safety findings are of enough concern that there’s unlikely to be a future for this drug at those higher doses,” Bergmark said. “For example, in the highest dose we studied, there was a 76% increase in liver fat, and quite frequent liver enzyme elevations.”

Bergmark explained the TRANSLATE-TIMI 70 data is proof of the benefit of clinical trials: “This is evidence that the science works,” he said. Nonetheless, he noted the variety of ongoing clinical research into lipid-targeting drugs for cardiovascular event prevention.

“This is just one among many, and as this broadens out, I think we’re going to start to see a lot of different ways to understand how to best approach lipid-based risk for patients,” he said.

Bergmark also highlighted some promising lipid-lowering agents, as well as the state of assessment into lipoprotein A (Lp[a])-targeting drugs and how that may better the field of cardiovascular prevention.

“We are going to learn a lot more about the specific importance of different lipoproteins for different people, and I think over time develop a more personalized, nuanced approach to this,” he said.

The study, “Effect Of Vupanorsen On Non-high-density Lipoprotein Cholesterol Levels In Statin-treated Patients With Elevated Cholesterol – TRANSLATE-TIMI 70,” was presented at ACC 2022.