Ocean(a)-DOSE: Olpasiran Shows Promise for Lowering Lipoprotein(a)

Michelle O'Donoghue, MD, MPH

Data from the Ocean(a)-DOSE trial is providing clinicians with new insight into the offers of olpasiran for reducing lipoprotein(a) [Lp(a)] levels in patients with elevated baseline Lp(a) and atherosclerotic cardiovascular disease.

Presented at the American Heart Association 2022 Scientific Sessions, results of the phase 2 dose-finding study indicate use of the small interfering RNA, olpasiran, dosed 75 mg or greater every 12 weeks was associated with reduction in Lp(a) levels among more than 95% of patients receiving such a dose.

“In this trial, the siRNA olpasiran led to a profound and sustained reduction in the lipoprotein(a) concentration when administered every 12 weeks. In the context of this short-term trial of moderate size, the drug appeared to be safe. These findings provide the foundation for a large-scale evaluation that will be necessary to confirm a causal role for lipoprotein(a) in atherosclerotic cardiovascular disease,” wrote investigators.

As the understanding and knowledge base of lipid management has grown, Lp(a) has been identified as a risk factor for ASCVD, even among patients with controlled LDL-C levels. With this in mind, the randomized, double-blind, placebo-controlled, dose-finding OCEAN(a)-DOSE trial was launched. The trial enrolled patients with established ASCVD and a Lp(a) concentration of more than 150 nmol per liter.

Once enrolled, patients were then randomized to subcutaneous olpasiran 10 mg every 12 weeks, olpasiran 75 mg every 12 weeks, olpasiran 225 mg every 12 weeks, olpasiran 225 mg every 24 weeks, or matching placebo. Overall 281 patients were enrolled and underwent randomization in the trial, with 54, 58, 58, 56, and 55 individuals randomized to the placebo, 10 mg every 12 week, 75 mg every 12 weeks, 225 mg every 12 weeks, and 225 mg every 24 weeks arms of the trial, respectively.

The primary outcome of interest for the trial was the percent change in Lp(a) concentration from baseline to week 36, which investigators noted would be reported as the placebo-adjusted mean percent change. The trial also includes multiple safety outcomes of interest.

The 281 patients included in the trial had a mean age of 61.9±9.5 years, 32% were women, the median baseline Lp(a) was 260.3 nmol/L, and the median baseline LDL-C level was 67.5 mg/dL. Among the overall patient population, 88% wee on statin therapy at baseline, 52% were on ezetimibe, and 23% were on an PCSK9 inhibitor, with investigators noting 61% were using high-intensity statin therapy. Investigators also pointed out the trial population was generally representative of established populations of ASCVD, with regard to race and ethnicity.

At 36 weeks, results indicated Lp(a) concentrations had increased by a mean of 3.6% in the placebo group. In contrast, use of olpasiran therapy was associated with significant and substantial reductions of Lp(a) concentration in a dose-dependent manner, with placebo-adjusted mean percent changes of −70.5% with the 10-mg dose, −97.4% with the 75-mg dose, −101.1% with the 225-mg dose administered every 12 weeks, and −100.5% with the 225-mg dose administered every 24 weeks (P <.001 for all comparisons with baseline). Investigators highlighted the overall incidence of adverse event was similar across trial groups, with injection-site reactions the most common treatment-related adverse event.

“The findings of this trial show that olpasiran treatment markedly reduced the concentration of lipoprotein(a) in a dose-dependent manner and appeared to be safe. At higher doses, olpasiran therapy reduced the lipoprotein(a) concentration by more than 95%, as compared with placebo, with nearly all patients who received olpasiran having a lipoprotein(a) concentration of less than 125 nmol per liter,” wrote investigators. “Moreover, the pharmacodynamic effects of olpasiran were maintained throughout the administration interval when the drug was administered every 12 weeks.”

This study, “Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease,” was presented at AHA 22 and simultaneously published in the New England Journal of Medicine.