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April 03, 2022
2 min read
Source/Disclosures
Published by:
Bergmark BA, et al. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; April 2-4, 2022; Washington, D.C. (hybrid meeting).
Disclosures:
The TIMI Study Group received institutional grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark, Regeneron, Roche, Siemens Healthcare Diagnostics, The Medicines Company and Zora Biosciences. Bergmark reports receiving grant support through the Brigham and Women’s Hospital from AstraZeneca, Abbott Vascular, Ionis and Pfizer and consultant/personal fees from Abbott Vascular, Abiomed, Cardiovascular Systems Inc., Daiichi-Sankyo, Janssen, Philips, Quark and Servier.
WASHINGTON — Treatment with vupanorsen, a novel antisense oligonucleotide targeting hepatic ANGPTL3, achieved modest reductions in non-HDL at 24 weeks at all doses studied, according to results of the TRANSLATE-TIMI 70 trial.
Patients assigned vupanorsen at higher doses had increased rates of injection-site reactions, elevations in liver enzymes and dose-related increases in hepatic fat accumulation, researchers reported at the American College of Cardiology Scientific Session.
The TRANSLATE-TIMI 70 trial evaluated the effects of escalating doses of vupanorsen (Ionis) on non-HDL in adults with hyperlipidemia already on statin therapy. The trial enrolled 286 adults (mean age, 64 years, 44% women; 87% white) with baseline non-HDL levels of 100 mg/dL or more (median, 132 mg/dL) and triglycerides ranging from 150 mg/dL to 500 mg/dL (median, 216 mg/dL). Participants were randomly assigned to placebo or one of seven vupanorsen dose regimens for 24 weeks: 80 mg, 120 mg or 160 mg administered every 4 weeks or 60 mg, 80 mg, 120 mg or 160 mg every 2 weeks. Twenty-one percent of participants discontinued the study drug during the trial; however, 99% completed follow-up.
Brian A. Bergmark
The primary endpoint was percentage change from baseline in non-HDL at 24 weeks. Researchers observed reductions in non-HDL with all seven vupanorsen dose regimens compared with placebo, ranging from 22% in the group that received 60 mg every 2 weeks to 27.7% in the group that received 80 mg every 2 weeks (P for all < .001), Brian A. Bergmark, MD, cardiologist at Brigham and Women’s Hospital and investigator with the TIMI Study Group, said during a late-breaking clinical trial presentation.
For the secondary endpoints, outcomes with vupanorsen were as follows:
- 69.9% to 95.2% reduction in ANGPTL3 from baseline to 24 weeks;
- 41.3% to 56.8% reduction in triglycerides from baseline to 24 weeks;
- 14.5% to 16% reduction in LDL from baseline to 24 weeks; and
- 8.5% to 15.1% reduction in apolipoprotein B from baseline to 24 weeks.
“The effects of vupanorsen on LDL cholesterol and ApoB were more modest and without a clear dose-response,” the researchers wrote in the study, which was simultaneously published in Circulation. Only the higher reductions achieved significance, according to the researchers.
Participants assigned vupanorsen at higher doses had increased rates of injection-site reactions and elevated liver enzymes. The researchers also reported dose-related increases in hepatic fat function in the vupanorsen group.
“Many of these findings were not anticipated by genetic, preclinical and earlier clinical data,” Bergmark said. “Ultimately, this trial emphasizes the importance of rigorous evaluation of new lipid-lowering therapies and may provide mechanistic insight as additional metabolic targets are studied, going forward.”
Earlier research of vupanorsen dose regimens administered every 4 weeks or weekly for 6 months in patients with elevated triglycerides, type 2 diabetes and hepatic steatosis showed a reduction in triglycerides at 6 months and benefit on additional lipid parameters compared with placebo.
On Jan. 31, Pfizer and Ionis announced the discontinuation of the Pfizer-led clinical development program for vupanorsen. Pfizer will return development rights to vupanorsen to Ionis, from which it licensed the investigational therapy in a worldwide exclusive agreement in 2019, according to a press release. Pfizer made the decision after a thorough review of the TRANSLATE-TIMI 70 trial, noting that the magnitude of non-HDL and triglyceride reduction observed did not support continuation of the clinical development program for CV risk reduction or severe hypertriglyceridemia, according to the release.
References:
Perspective
Eileen M. Handberg, PhD, ARNP, BC, FACC
I was surprised by the amount of adverse events. I was not anticipating it to that degree, but that’s what research is about, especially in a dose-finding study.
You always hope that your hypothesis is correct when you are doing research. One would have thought the results would have gone in one direction, and that’s why the trial was done. But it did not. The drug has been withdrawn by Pfizer and given back to Ionis, so it’s not likely they will proceed. Maybe they have something else in the pipeline that is some slight variation and may obviate some of those risks that occurred.
There are a lot of different pathways that we’re now identifying in terms of lipids. It’s not just LDL. There is small interfering RNA work and now going after Lp(a) [for example]. Those are both on the lipid pathway. The thinking here is more broad strokes. People are exploring all the pathways and treatment targets.
Eileen M. Handberg, PhD, ARNP, BC, FACC
Professor of Medicine
University of Florida College of Medicine
Disclosures: Handberg reports no relevant financial disclosures.
American College of Cardiology
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