An investigational drug targeting a novel cholesterol pathway has shown disappointing results in the TRANSLATE-TIMI 70 phase 2b study.
Vupanorsen is an antisense oligonucleotide targeting hepatic angiopoietin-like protein 3 (ANGPTL3), a protein that inhibits enzymes involved in the metabolism of triglyceride and cholesterol. Inhibition of ANGPTL3 is one of several novel targets for lowering triglycerides and non-HDL cholesterol.
Dr. Brian Bergmark
Results of the TRANSLATE-TIMI 70 study were presented at the annual scientific sessions of the American College of Cardiology by Brian Bergmark, MD, a cardiologist at Brigham and Women’s Hospital, Boston. They were also simultaneously published online in Circulation.
“While vupanorsen significantly reduced triglycerides and non-HDL cholesterol, the reduction in non-HDL cholesterol of 22%-27% was not to a degree that was clinically meaningful for cardiovascular risk reduction, and there were also some potentially important safety issues,” Dr. Bergmark said in an interview.
Pfizer has announced that, after reviewing the results of this study, it is discontinuing development of vupanorsen and will return rights to Ionis, from which it licensed the investigational therapy in 2019.
In response to a question at an ACC press conference on whether there could be any future for the drug, Dr. Bergmark said that “the degree of lipid lowering was not as much as what had been suggested was potentially possible by acting on this pathway, and then there are the additional safety concerns. So, for the specific question of what we were looking at – cardiovascular risk reduction by impacting non-HDL cholesterol and apo [apolipoprotein] B – the modest efficacy paired with the safety concerns does not look favorable for future development of this drug.”
But he added: “Whether some other person or company wants to think about triglyceride lowering and try to find a dose that is a bit safer, that is not for me to say.”
In his ACC presentation, Dr. Bergmark explained that ANGPTL3 is a protein secreted by the liver that inhibits lipases, including lipoprotein lipase. Loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids and a monoclonal antibody targeting ANGPTL3, evinacumab (Evkeeza, Regeneron), is approved as an intravenous infusion for the treatment of familial hypercholesterolemia. Vupanorsen is a second-generation antisense oligonucleotide targeting hepatic ANGPTL3 messenger RNA with a potential role for cardiovascular risk reduction.
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A previous phase 2a study of vupanorsen in patients with hypertriglyceridemia, hepatic steatosis, and type 2 diabetes mellitus showed significant reductions in triglycerides at all doses studied, as well as reductions in non-HDL cholesterol at the highest doses (80 mg per month given by subcutaneous injection).
Dr. Bergmark noted that, because a potential cardiovascular benefit of vupanorsen would best be reflected by its effects on non-HDL cholesterol, the current TRANSLATE-TIMI 70 trial was designed to assess the effect of escalating doses of vupanorsen on non-HDL cholesterol levels in statin-treated adults with hyperlipidemia.
For the study, 286 adults with non-HDL cholesterol levels of 100 mg/dL or greater (median, 132 mg/dL) and triglyceride levels of 150-500 mg/dL (median, 216 mg/dL) who were receiving statin therapy were randomly assigned to placebo or one of seven vupanorsen dose regimens (80, 120, or 160 mg every 4 weeks or 60, 80, 120, or 160 mg every 2 weeks). All doses were given by subcutaneous injection.
The study population was said to reflect “a typical cohort intended for cardiovascular risk reduction, with type 2 diabetes in approximately one-half of patients and prevalent atherosclerotic cardiovascular disease in a substantial portion,” the researchers wrote in the published report.
The primary endpoint was placebo-adjusted percentage change from baseline in non-HDL cholesterol at 24 weeks. Secondary endpoints included placebo-adjusted percentage changes from baseline in triglycerides, LDL cholesterol, apo B, and ANGPTL3.
Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL cholesterol ranging from 22.0% in the group receiving 60 mg every 2 weeks to 27.7% in the group receiving 80 mg every 2 weeks, but there did not appear to be a dose response.
Regarding additional lipid endpoints, vupanorsen reduced triglyceride levels in a dose-dependent manner, ranging from 41.3% in the group receiving 120 mg every 4 weeks to 56.8% in the group receiving 160 mg every 2 weeks.
The effects of vupanorsen on LDL cholesterol and apo B were more modest and without a clear dose response. Vupanorsen also lowered HDL cholesterol levels at all doses studied, and there was no significant change in high-sensitivity C-reactive protein at any dose.
Liver enzymes and hepatic fat increases of concern
In terms of safety, vupanorsen treatment was linked to liver enzyme elevations; more than three-times elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively). Injection site reactions were also an issue, including recall reactions at sites of previous injections when subsequent injections were given. In addition, there was a dose-related increase (up to 76%) in hepatic fat fraction.
In the Circulation paper, the researchers say it is unclear whether the increases in hepatic fat fraction and liver enzymes reflect a metabolic effect of vupanorsen specifically or an off-target effect resulting from hepatic targeting of ANGPTL3. “Regardless, these are medically meaningful findings with important safety ramifications,” they wrote.
They pointed out that, whereas the reduction in ANGPTL3 levels increased with total monthly dose of vupanorsen, there was no clear dose-response reduction in LDL cholesterol, apo B, or non-HDL cholesterol.
In comparison, evinacumab, a monoclonal antibody against ANGPTL3 that is thought to cause near-total suppression of ANGPTL3 activity, reduces apo B levels by more than 40% in adults with refractory hypercholesterolemia or homozygous familial hypercholesterolemia.
Asked why vupanorsen showed less of an effect on non-HDL cholesterol than evinacumab, Dr. Bergmark suggested that the monoclonal antibody may achieve greater inhibition of ANGPTL3. “It may be that near complete suppression is needed to obtain clinically meaningful reductions in apo B and non-HDL cholesterol. That is a speculative and simplistic explanation,” he commented.
Conversely, reductions in triglycerides with vupanorsen showed a dose-response relationship, mirroring the reduction in ANGPTL3 and consistent with the expected increases in lipoprotein lipase activity, the researchers reported.
They note that the “relatively muted effect on apo B levels” suggests that vupanorsen is primarily decreasing the triglyceride and, to a lesser extent, cholesterol content of very low-density lipoprotein cholesterol particles rather than reducing the number of such particles.
“These observations have important implications for the potential ability of this mechanism to reduce lipid-mediated cardiovascular risk, which largely appears to be a function of the number of ApoB-containing lipoproteins,” they said.
Dr. Pradeep Natarajan
Designated discussant of the study at the ACC late-breaking session, Pradeep Natarajan, MD, director of preventive cardiology at Massachusetts General Hospital in Boston, asked Dr. Bergmark what minimum degree of non-HDL cholesterol reduction would be compelling for a new drug to be considered for wide-scale use.
Dr. Bergmark replied there was no clear to answer to that question, as it would depend on many factors, including the risk of the population and the time horizon involved. But he added: “I think a minimum of at least a 30%-40% reduction in non-HDL cholesterol would be needed for a meaningful reduction in cardiovascular risk across a variety of settings.”
The TRANSLATE-TIMI 70 study was funded by Pfizer. Dr. Bergmark is a member of the TIMI Study Group, which has received institutional grant support through Brigham and Women’s Hospital from numerous pharmaceutical companies. Dr. Bergmark also reported receiving grant support through Brigham and Women’s Hospital from Pfizer, Ionis, AstraZeneca, and Abbott Vascular and consulting/personal fees from Abiomed, CSI, Philips, Abbott Vascular, Servier, DaiichiSankyo, Janssen, and Quark.
A version of this article first appeared on Medscape.com.