A growing number of genetic studies support a causal role for lipoprotein(a) in atherosclerotic cardiovascular disease. Olpasiran, a small interfering RNA that reduces lipoprotein(a) synthesis in the liver, was found in a phase 1 trial to reduce lipoprotein(a) concentration in a dose-dependent manner, and its effect persisted for three to six months.

Michelle L. O’Donoghue, MD, MPH, a senior investigator in the Thrombolysis in Myocardial Infarction (TIMI) Study Group in the Division of Cardiovascular Medicine at Brigham and Women’s Hospital and the McGillycuddy-Logue distinguished chair in Cardiovascular Medicine, Marc S. Sabatine, MD, MPH, chair of the TIMI Study Group and the Lewis Dexter, MD distinguished chair in Cardiovascular Medicine, and colleagues recently completed the phase 2 dose-finding OCEAN(a)-DOSE (TIMI 67) trial of olpasiran. They report in The New England Journal of Medicine that olpasiran was associated with dose-dependent reductions in lipoprotein(a), with decreases of more than 95% when administered every 12 weeks at a dose of 75 mg or 225 mg.

Methods

The randomized, double-blind, placebo-controlled trial was conducted at 34 sites in seven countries. It was sponsored by Amgen and designed by the TIMI Study Group and sponsor.

Adults 18 to 80 years of age were eligible if they had a serum lipoprotein(a) concentration >150 nmol/L (approximately 70 mg/dL) and a history of atherosclerotic cardiovascular disease (coronary heart disease, peripheral artery disease, or atherosclerotic cerebrovascular disease).

281 patients (68% male, mean age 62) were randomly assigned between July 28, 2020, and April 26, 2021, to receive the following:

• 10 mg olpasiran every 12 weeks
• 75 mg olpasiran every 12 weeks
• 225 mg olpasiran every 12 weeks
• 225 mg olpasiran every 24 weeks
• Matching placebo

All told, 227 participants received olpasiran and 54 received placebo. Both olpasiran and placebo were administered subcutaneously. After 48 weeks of treatment, patients participated in a safety follow-up period without further administration of olpasiran or placebo for at least 24 weeks.

Primary Endpoint

The primary endpoint was the percent change in the lipoprotein(a) concentration from baseline to week 36. In the placebo group, the mean change was +3.6%.

In contrast, there were substantial reductions in all olpasiran groups, with reductions from a baseline of >95% with the highest doses. Thus, the placebo-adjusted mean percent changes were (P<0.001 for all comparisons with baseline):

−71% with the 10-mg dose every 12 weeks

−97% with the 75-mg dose every 12 weeks

−101% with the 225-mg dose every 12 weeks

−101% with the 225-mg dose every 24 weeks

There was limited interpatient variability in pharmacodynamic response; at higher doses of olpasiran, nearly all patients had a lipoprotein(a) concentration <125 nmol/L at 36 weeks.

Secondary Endpoints

At 36 weeks, the placebo-adjusted mean percent changes in other lipids across olpasiran dose levels were:

• LDL cholesterol concentration—Ranged from −23% to −25%
• Apolipoprotein B concentration—Ranged from −17% to −19%

The other secondary endpoint was the placebo-adjusted mean percent change in the lipoprotein(a) concentration with olpasiran at 48 weeks, which ranged from −69% to −101%.

Safety

In the context of a short-term trial with a moderate sample size, olpasiran appeared to be safe. The overall incidence of adverse events, serious adverse events, and adverse events leading to discontinuation was similar across the trial groups. Injection-site and hypersensitivity reactions were more common with olpasiran than placebo; these effects were primarily transient and localized and infrequently led to drug discontinuation.

Next Steps

The next step is a larger, longer trial to evaluate the clinical efficacy of olpasiran in reducing the risk of major adverse cardiovascular events. This trial, OCEAN(a)-OUTCOMES (TIMI 75), has just started enrolling patients.