Post-hoc Analysis Offers Hope for Novel Cholesterol Drug

Liam Davenport

June 08, 2022

MILAN, Italy — The antisense oligonucleotide vupanorsen substantially reduces very low density lipoprotein (VLDL) and remnant cholesterol levels in patients with raised lipids despite statin therapy, suggests a subanalysis of TRANSLATE-TIMI 70 that appears to offer more hope than the primary study findings.

Vupanorsen targets hepatic angiopoietin-like protein 3 (ANGPTL3), which inhibits enzymes involved in triglyceride and cholesterol metabolism.

Earlier this year, headline data from TRANSLATE-TIMI 70 suggested that the drug reduced triglycerides and non-high-density lipoprotein (HDL) cholesterol to a degree that was significant but not clinically meaningful for cardiovascular risk reduction.

Moreover, as reported by | Medscape Cardiology, there were safety concerns over increases in liver enzymes among patients taking the drug, as well as dose-related increases in hepatic fat.

As a result, Pfizer announced that it would discontinue its clinical development program for vupanorsen and return the development rights to Ionis, following the signing of a worldwide exclusive agreement in November 2019.

Now, Nicholas A. Marston, MD, MPH, cardiovascular medicine, Brigham and Women's Hospital, Boston, Massachusetts, presented a post-hoc analysis of the phase 2b study, showing that the drug reduces VLDL and remnant cholesterol levels by up to 60%.

These were closely tied to reductions in ANGPTL3 levels, although substantial reductions in cholesterol levels were achieved even at less than maximal reductions in ANGPTL3, where the impact on safety outcomes was reduced.

Marston said that lower doses of vupanorsen, where the safety effects would be less, or other drugs that inhibit ANGPTL3, "may have an important role in patients with residual dyslipidemia despite current therapy."

The results were presented at the 90th European Atherosclerosis Society Congress on May 23.

Marston told | Medscape Cardiology that some of the reductions they saw with the lower doses of vupanorsen were "just as good as any other therapy, and the safety profile was...much better than at the highest dose."

They wanted to pursue the subgroup analysis, despite Pfizer's announcement, partly to "learn something in terms of the potential efficacy of the ANGPTL3 pathway in general."

Marston said that Ionis is now focused on ANGPTL3, and the current results suggest that it "works very well," so if other drugs are able to achieve the same efficacy as vupanorsen "but without the effects," then it may "get elbowed out."

Børge G. Nordestgaard, MD, PhD, Herlev and Gentofte Hospital, Copenhagen, Denmark, who was not involved in the study, called the findings "very encouraging."

He told | Medscape Cardiology that being able to reduce low density lipoprotein (LDL) cholesterol as well as VLDL and remnant cholesterol is "exactly what I would be dreaming about" with a drug like vupanorsen.

Nordestgaard nevertheless underlined that "one would have to look carefully" at the safety of the drug.

"If it was my money, I would certainly try to look into if this was some sort of transient thing. Even when they started talking about statins, there was also this transient increase in alanine transaminase that seems to go away after a while," he said.

"But of course, if this was persistent and triglycerides in the liver kept accumulating, then it's a problem," Nordestgaard added, "and then you would need to have some sort of thinking about whether you could couple it with something that got rid of the liver fat."

He also agreed with Marston that, even if vupanorsen does not clear all hurdles before making it to market, the approach is promising.

"The target," Nordestgaard said, seems "fantastic, from my point of view anyway."

Marston explained that VLDL cholesterol, remnant cholesterol, and triglycerides are "surrogates for triglyceride-rich" lipoproteins, and that they are "increasingly recognized" as cardiovascular risk factors.

He highlighted that currently available therapies achieve reductions of these compounds of between 30% and 50%.

TRANSLATE-TIMI 70 included adults on stable statin therapy who had a triglyceride level of 150 mg/dL to 500 mg/dL and a non-HDL cholesterol level ≥ 100 mg/dL.

The participants were randomly assigned to one of six 2- or 4-week dosing schedules of vupanorsen or placebo and followed up over 24 weeks for a series of primary and additional endpoints, as well as safety outcomes.

The team recruited 286 individuals, who had a median age of 64 years; 44% were female. The majority (87%) were white.

The mean body mass index was 32 kg/m2, 50% had diabetes, 13% had experienced a prior myocardial infarction, and 51% were receiving high-intensity statins.

As previously reported, vupanorsen was associated with a reduction in non-HDL cholesterol vs placebo of 22% to 28%, alongside a 6% to 15% reduction in apolipoprotein B levels and an 8% to 16% reduction in LDL cholesterol.

In contrast, Marston showed that the various dosing schedules of the drug were associated with reductions in levels of VLDL cholesterol of 52% to 66% vs placebo at 24 weeks.

Over the same period, remnant cholesterol levels were lowered by 42% to 59% vs placebo, and triglycerides were reduced by 44% to 57% in patients given vupanorsen.

There were also reductions in ANGPTL3 levels of 70% to 95%.

Subgroup analysis indicated that the effect of vupanorsen was seen regardless of age, sex, body mass index, presence of diabetes, baseline triglycerides, and intensity of statin therapy.

Marston highlighted that the reductions in triglycerides, VLDL cholesterol, and remnant cholesterol levels were directly related to those for ANGPTL3 levels, but that the reductions remained meaningful even at less than maximal reductions in ANGPTL.

For example, even when ANGPTL3 levels were reduced by 70%, there were 50% reductions in triglyceride levels, 70% reductions in VLDL cholesterol levels, and a 50% drop in remnant cholesterol levels.

This, he noted, is important given that safety signals such as increases in alanine transaminase and hepatic fat occurred in a dose-dependent manner with ANGPTL3 reductions and were "most pronounced" only at the highest level of ANGPTL3 reduction.

The TRANSLATE-TIMI 70 study was sponsored by Pfizer. Marston disclosed relationships with Pfizer, Amgen, Ionis, Novartis, and AstraZeneca. Nordestgaard disclosed relationships with AstraZeneca, Sanofi, Regeneron, Akcea, Ionis, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics.

European Atherosclerosis Society (EAS) 2022. Presented May 23, 2022.

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