Issue: December 2022
Fact checked byErik Swain

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November 07, 2022
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Olpasiran cut Lp(a) levels by more than 95% in patients with atherosclerotic CVD

Issue: December 2022
Fact checked byErik Swain
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CHICAGO — Olpasiran, a small interfering RNA agent directed to the liver, yielded substantial and sustained reductions in lipoprotein(a) concentrations among patients with established atherosclerotic CVD in the phase 2 OCEAN(a)-DOSE study.

“Olpasiran ... dosed at 75 mg or higher every 12 weeks reduces Lp(a) concentration by more than 95% in patients with established atherosclerotic cardiovascular disease,” Michelle L. O’Donoghue, MD, MPH, FAHA, cardiovascular medicine specialist and senior investigator of the TIMI Study Group at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, said during a presentation at the American Heart Association Scientific Sessions.

Cholesterol_AdobeStock
Olpasiran yielded substantial and sustained reductions in lp(a) concentrations among patients with established ASCVD.
Source: Adobe Stock

Dose-dependent reductions

In this study, patients were randomly assigned to receive placebo or one of four doses of subcutaneous olpasiran (Amgen). Olpasiran reduced Lp(a) concentrations in a dose-dependent manner, the researchers reported. The primary endpoint, percent change in Lp(a) concentration from baseline to 36 weeks, was as follows:

  • –70.5% with olpasiran 10 mg every 12 weeks;
  • –97.4% with olpasiran 75 mg every 12 weeks;
  • –101.1% with olpasiran 225 mg every 12 weeks;
  • – 100.5% with olpasiran 225 mg every 24 weeks; and
  • 3.6% increase with matching placebo

The P value for the primary endpoint was < .001 for all comparisons compared with baseline.

In other results, the percent of patients who achieved an Lp(a) concentration below 125 nmol/L was 66.7% with the 10 mg dose every 12 weeks, 100% with the 75 mg and 225 mg doses every 12 weeks and 98.1% with the 225 mg dose every 24 weeks, according to the results. No patients in the placebo group achieved that goal.

Adverse events were similar in the olpasiran and placebo groups. The most common treatment-related adverse events were injection-site and hypersensitivity reactions, which were mild and resolved without treatment, according to O’Donoghue.

Michelle L. O’Donoghue

“To date, the drug appears both safe and well tolerated,” O’Donoghue said during the late-breaking science presentation.

OCEAN(a)-DOSE was a randomized, double-blind, placebo-controlled, dose-finding, phase 2 trial. The 281 patients enrolled had established ASCVD and Lp(a) concentrations greater than 150 nmol/L. At baseline, the median Lp(a) concentration was 260.3 nmol/L and median LDL concentration was 67.5 mg/dL. Eighty-eight percent of patients were also on statin therapy, 52% on ezetimibe and 23% on a PCSK9 inhibitor at baseline. The mean age of those enrolled was 62 years, 32% were women and the majority were white.

The study was conducted at 34 sites in seven countries.

“These findings set the foundation for phase 3 testing scheduled to commence later this year,” O’Donoghue said.

‘Hope is in sight’

“Hope is in sight” for patients with elevated levels of Lp(a), Stephen J. Nicholls, MBBS, PhD, director of Monash Heart and professor at Monash University in Melbourne, Australia, said during a discussion of the trial.

Nicholls said there remain many unknowns about Lp(a), including whether lowering Lp(a) will reduce CV risk, how the presence of other factors such as inflammation influence risk, whether reducing it greatly will have long-term consequences, whether substantial reductions will increase the rate of diabetes; and whether there will be consequences to stopping therapy.

Nicholls said multiple trials may be needed to answer these unknown questions.

“As we move forward and the field is excited, and we have therapeutics in this space, it will be just as important for us to increase the testing of Lp(a) in clinical practice,” Nicholls said.

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