Olpasiran Cuts Lp(a) but Not Inflammatory Markers: OCEAN(a)-DOSE

The novel small interfering RNA (siRNA) drug olpasiran (Amgen) can successfully lower lipoprotein(a) as well as oxidized phospholipids (OxPL), but this does not translate into a reduction in inflammatory biomarkers, according to new findings from the OCEAN(a)-DOSE trial.

How Lp(a)-lowering improves cardiovascular risk, even in patients with low LDL cholesterol, remains unclear, but experts have long assumed that decreasing it would interrupt the inflammatory pathway. Other research has hinted that OxPLs might play a substantial role in atherosclerotic cardiovascular disease (ASCVD), such that trimming them down is desirable.

The new data challenge that hypothesis by showing no change in high-sensitivity interleukin 6 (hs-IL-6) or C-reactive protein (hs-CRP) among 272 patients with ASCVD who achieved successful Lp(a)-lowering with olpasiran over 36 weeks.

“There was a concept that has been promulgated that this pathway was linear: high Lp(a), high oxidized phospholipids, high levels of inflammation, and more cardiovascular events,” lead author Robert S. Rosenson, MD (Mount Sinai Hospital, New York, NY), told TCTMD. “If you read the literature, everybody’s convinced that this is the pathway, and we’re demonstrating that this is not the pathway.”

The findings were published online as a brief report this week in JAMA Cardiology.

No Link to Inflammation

For the study, Rosenson and colleagues included 272 participants from OCEAN(a)-DOSE (median age 62 years; 31.6% female) with ASCVD and baseline Lp(a) levels of more than 150 nmol/L. The study randomized patients to one of four doses of olpasiran or placebo.

Over the study period, median OxPL on apolipoprotein B (OxPL-apoB) concentration dropped from 26.5 nmol/L by between 51.6% and 92.3% depending on the olpasiran dose used compared with placebo. By 48 weeks, reductions were between 50.8% and 104.7% (P < 0.001 for all). These findings were consistent across patient subgroups based on age, sex, race, baseline Lp(a), baseline LDL cholesterol, and statin use.

Further, the researchers found that the percent reduction in Lp(a) correlated with that of OxPL-apoB in patients treated with olpasiran (r = 0.79; P < 0.001).

No significant impact of olpasiran treatment was seen, however, on either hs-CRP or hs-IL-6.

“This is really a transformational study in terms of challenging widely held concepts,” Rosenson said. He acknowledged that he was surprised not to see an association between Lp(a)-lowering and inflammatory biomarkers.

“It means that there’s more work that’s needed to understand the biology of Lp(a) and how [it] increases cardiovascular events,” he said. “We need to look more broadly beyond interleukin 6 and CRP to other inflammatory proteins that may be affected by Lp(a).”

Additionally, Rosenson continued, the fact that OxPLs and Lp(a) levels “mirrored each other” raises the question of whether future studies should continue to measure them, since “you’re not gaining any more information from that biomarker.”

‘Head-Scratching Findings’

For Karol Watson, MD, PhD (UCLA Health, Los Angeles, CA), who commented on the study for TCTMD, the “head-scratching” findings don’t change the fact that Lp(a) contributes to “nature’s perfect recipe for a heart attack.”

While it’s possible that experts have misunderstood the mechanism behind why that is, the new data might also indicate that “circulating markers are just a bad way to really assess what’s going on in the vessel wall,” she said. “If you’re decreasing oxidized phospholipids on apoB, that’s intracellular—that’s right in the vessel wall. That’s not going to really show up in the circulation so much. So maybe it’s just a matter of measuring the right markers in the wrong place.”

However, Watson continued, “it kind of doesn’t matter, because in the end, all that matters is outcomes. We just need the clinical trials.”  Studying atherosclerosis is “just so difficult, she said. “You tweak one thing, and something else is affected. So it’s really hard to drill down and figure out what’s going to be the effect of altering one lipoprotein.”

The ongoing OCEAN(a) cardiovascular outcomes trial will provide a clearer picture of the effect of Lp(a)-lowering with olpasiran and “potentially [show] whether changes in oxidized phospholipid on the Lp(a) provide any incremental information at all beyond the Lp(a)-lowering,” Rosenson said.

“Right now, I think that many of us who do work on lipoprotein(a) need to reexamine these concepts and further explore pathways that may trigger the higher cardiovascular events with lipoprotein(a), as an example, when compared to an LDL particle,” he suggested.