乌鸦传媒

Higher than yet-tested doses of the novel ANGPTL3-targeting antisense agent vupanorsen modestly reduced non-HDL cholesterol and triglycerides in the TRANSLATE-TIMI 70 trial, but with a concerning safety profile that appears to have killed development.

Vupanorsen reduced non-HDL cholesterol from baseline to 24 weeks by 22.0% to 27.7% more than placebo across the doses tested, with all being significant at P<0.001, reported Brian A. Bergmark, MD, of Brigham and Women's Hospital in Boston, at the American College of Cardiology (ACC) meeting, held virtually and in Washington.

Triglycerides fell in a dose-dependent manner, ranging from 41.3% to 56.8% with the agent versus placebo from baseline to 24 weeks (all P<0.001), Bergmark's group reported simultaneously in .

LDL and other lipid parameters were reduced at some doses, but apolipoprotein B (ApoB) showed only a modest 6.0%-15.1% reduction without a stronger effect at higher doses.

The benefits were underwhelming, commented Eugene Yang, MD, of the University of Washington in Seattle, and chair of the ACC Prevention Council.

"This drug seems to be far less effective, even at reducing triglycerides, than evinacumab" (Evkeeza), the ANGPTL3-targeted monoclonal antibody, he told 乌鸦传媒.

These findings suggest "that vupanorsen is primarily decreasing the triglyceride, and, to a lesser extent, cholesterol content of very-low-density lipoprotein particles rather than reducing the number of such particles," the researchers wrote. "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."

Vupanorsen is a second-generation antisense oligonucleotide inhibiting synthesis of ANGPTL3 in the liver, where it blocks breakdown of lipids and triglyceride-rich lipoproteins. Genetics pointed to it as a potential treatment, as loss-of-function variants in correlate with lower triglycerides, LDL, and coronary artery disease rates.

A previous trial showed promise in clinical use but only tested total monthly doses up to 80 mg.

Bergmark and colleagues conducted a phase IIb trial that tested higher doses, randomizing 286 patients (median age 64, 44% female, 13% non-white) with elevated non-HDL cholesterol and triglycerides to subcutaneous injections of placebo or vupanorsen at doses of 80-160 mg every 4 weeks or 60-160 mg every 2 weeks. Median baseline non-HDL cholesterol was 132.4 mg/dL, while median triglycerides were 216.2 mg/dL.

The results were "observed on a background of statin therapy, including in those on a high-intensity statin regimen, and the study population reflects 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 noted.

Serious adverse events weren't deemed related to the study drug, but there were several safety signals with vupanorsen:

• Elevations in alanine aminotransferase or aspartate aminotransferase more than three times the upper limit of normal were more common, especially at higher total monthly doses, (44.4% with 160 mg every 2 weeks, with 38.9% having an abnormal repeat value within 7 days)
• Dose-related increase in hepatic fat fraction up to 76%
• Antidrug antibodies in 30.2%, although with no apparent treatment impact
• Injection site reactions in 20.2%, including reactions at the previous site of injection upon subsequent injections elsewhere
• Reduced HDL cholesterol at all doses

The liver findings don't readily fit the understanding of this metabolic pathway, the researchers pointed out, "although a significant increase in hepatic fat fraction was also seen in the 80 mg every 4 weeks dose arm in the phase 2a study of vupanorsen ... Fibrates, which also increase lipoprotein lipase activity, have shown a strong trend toward increasing hepatic fat."

Whatever the mechanism, "these are medically meaningful findings with important safety ramifications," Bergmark and colleagues wrote.

The liver function test signals were "quite significant" and concerning for potentially leading to liver failure with sustained use, Yang agreed. "They have a lot of things to be worried about."

However, there were no confirmed cases of reduced renal function or thrombocytopenia with vupanorsen, which had been seen with some first-generation antisense oligonucleotides.

How vupanorsen will stack up against agents in development with adjacent metabolic targets, such as apolipoprotein C3 or lipoprotein lipase, remains to be seen.

Yang noted that the "safety signal when you weigh the potential benefits and the risk...it's clear that you have to do probably every 4-week dosing. And with the modest effects, is that enough to push them on to continuing to a phase III trial? I don't know."

"We're trying to reduce residual risk," but these were "significant safety signals," said Eileen Handberg, PhD, ARNP, of the University of Florida in Gainesville. "It would be hard to think this would go forward."

Indeed, Pfizer and Ionis Pharmaceuticals in January that they were dropping Pfizer-led clinical development of vupanorsen, and returning all development rights to Ionis.

While there's no reasonable future for the drug in cardiovascular risk reduction, there's still the possibility that a safe dose could be found for triglyceride lowering, Bergmark said at an ACC press conference.

The "emphasizes the importance of rigorous evaluation of new lipid-lowering therapies and may provide mechanistic insight as additional metabolic targets are studied going forward," Bergmark concluded.

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