Olpasiran Benefit Beyond Blocking Lp(a)

An ribonucleic acid (RNA) inhibitor, olpasiran (Amgen), which has shown it can lower lipoprotein(a) [Lp(a)] levels in patients with cardiovascular disease (CVD), has demonstrated in a phase 2 trial that its use can also lead to a significant and sustained reduction in oxidized phospholipids, according to new data.

A phase 3 outcomes trial for olpasiran has begun and will determine whether the lower numbers translate to fewer cardiovascular events.

The latest data reinforce that Lp(a) appears to be the major carrier of oxidized phospholipids, key drivers of inflammation and atherosclerosis.

Olpasiran’s effects on oxidized phospholipids and inflammation markers were not known. Findings of the new study, led by Robert Rosenson, MD, professor of medicine in Cardiology at the Icahn School of Medicine at Mount Sinai in New York City, were published in JAMA Cardiology.

The randomized OCEAN(a)-DOSE trial enrolled 281 patients with CVD and Lp(a) levels > 150 nmol/L (60 mg/dL). Those Lp(a) levels are believed to promote clotting and inflammation, significantly increasing the risk for heart attack, stroke, aortic stenosis, and peripheral artery disease. Participants were randomized to receive one of four regimens of subcutaneous doses of olpasiran vs placebo.

“Our study is the first clinical trial to investigate the association between oxidized phospholipids on lipoprotein(a) and inflammatory mediators,” Rosenson said in a statement.

The research team reported that the group that received ≥ 75 mg of olpasiran every 12 weeks had ≥ 95% reduction in Lp(a) than the placebo group at 36 weeks. At week 36, Lp(a) increased by an average of 3.6% in the placebo group, whereas there were substantial reductions of Lp(a) levels in all of the olpasiran groups. Adverse event rates were similar in the olpasiran and placebo cohorts.

The new data included 272 participants and “revealed that olpasiran led to a significant and sustained reduction in oxidized phospholipids on apolipoprotein B,” Rosenson said. At the highest dose (225 mg given every 24 weeks), the reduction in oxidized phospholipids on apolipoprotein B was 93.7%. “We observed no significant effects of olpasiran, however, on the secretion of the proinflammatory cytokine interleukin-6 or C-reactive protein compared to the placebo group.”

During the treatment phase, a dose-dependent reduction in oxidized phospholipids on apolipoprotein B was seen as the placebo-adjusted mean percentage.

“The field of cardiology is enthusiastic about the potential for Lp(a)-directed therapy to be another commonly used tool to improve patient outcomes,” Seth Martin, MD, professor of medicine in the Division of Cardiology at Johns Hopkins Medicine in Baltimore told Medscape Cardiology.

He said attention has been increasingly focused on Lp(a), and olpasiran is one of about five promising Lp(a)-directed agents. “The one, in addition to olpasiran, that’s farthest along is pelacarsen (Novartis),” he said.

“This paper is really fascinating because it looks at this biomarker of phospholipids. This paper will put that even more on the radar for analyses that come out from the large cardiovascular outcome trials,” Martin said.

Phase 3 will reveal whether olpasiran’s reductions translate to clinical benefit.

“It all comes down to the phase 3 trial,” said Scott Feitell, DO, director of heart failure at Rochester Regional Health in Rochester, New York. “The early trials were not powered to tease out cardiovascular benefit. It will either be a home run — this is next big thing — or it’s a complete and total dud and we’re going down the wrong pathway and it won’t have a direct benefit for patients.” Phase 3 results may also confirm or deny that pursuing development of drugs that lower Lp(a) is the proper pathway, he said. Lp(a) is not routinely checked currently, he pointed out.

Interest in this area is high because it’s been known for more than two decades that having an elevated Lp(a) is a good predictor of CVD risk. The challenge is that traditional medications for lowering cholesterol, such as statins, and diet and exercise don’t seem to reduce it, Feitell said.

This study shows that lowering Lp(a) was accompanied by a lowering of phospholipids in the bloodstream. “Whether that’s clinically significant at this point — the jury is still out,” he said.

Rosenson said as the OCEAN trial advances, it “will enable us to more accurately select patients for future trials who are likely to show an anti-inflammatory response from selective RNA inhibitors of lipoprotein(a).”

This research was done in collaboration with the TIMI Study Group and sponsored by Amgen, Inc. Rosenson reported receiving grants and personal fees from Amgen during the conduct of the study; grants from 89bio, Arrowhead Pharmaceuticals, Eli Lilly and Company, Merck Sharp & Dohme, Novartis Pharmaceuticals, Novo Nordisk, and the US National Institutes of Health; personal fees from Arrowhead Pharmaceuticals, CRISPR Therapeutics, Editas Medicine, Eli Lilly and Company, Intercept Pharmaceuticals, Kowa America Corporation, Life Extension, Lipigon, New Amsterdam, Novartis Pharmaceuticals, Organon, Precision Biosciences, Regeneron, Rona Therapeutics, UltraGenyx, Verve Therapeutics, Viatris, and Wolters Kluwer; and holding stock in MediMergent outside the submitted work. Full disclosures for the other authors are listed with the full paper. Martin has been a paid consultant to multiple pharmaceutical companies that make lipid-lowering drugs, including Amgen and Novartis. Feitell had no relevant financial disclosures.