Profound and Sustained Reductions in Lipoprotein(a) With Olpasiran

Treatment with olpasiran — a small interfering RNA product targeting lipoprotein(a), or Lp(a), synthesis — led to a profound and sustained reduction in Lp(a) concentration when administered every 12 weeks, as evidenced by a new phase II study presented at the American Heart Association (AHA) annual meeting. The findings were also simultaneously published online in the New England Journal of Medicine.

In this exclusive MedPage Today video, lead author Michelle O’Donoghue, MD, a cardiovascular medicine specialist at Brigham and Women’s Hospital in Boston, discusses the OCEAN(a)-DOSE TIMI 67 trial.

Following is a transcript of her remarks:

So OCEAN(a)-DOSE was a phase II dose-ranging study that enrolled patients with established atherosclerotic disease and elevated Lp(a) concentrations and randomized them to one of four active doses of olpasiran or matching placebo. In all, 281 patients were randomized. There were three doses of olpasiran that were dosed every 12 weeks. And then there was a fourth exploratory dose that was administered every 24 weeks. And the primary endpoint for the study was the percent change in Lp(a) at 36 weeks.

In short, what we observed was that for patients who had been randomized to placebo there was a slight upward drift in Lp(a) concentration over time, a rise of about 3.6%. And I mention this only because it has caught some people’s eye that some of the doses of olpasiran reduced Lp(a) concentration by greater than 100%. But that is explained by the fact that it’s a placebo-adjusted percent change.

So what we observed were that the higher doses of olpasiran, for instance the 75 mg and 225 mg doses administered every 12 weeks, reduced Lp(a) concentration by more than 95%. So just a really marked as well as sustained effect on Lp(a) that was maintained throughout follow-up.

The dose that was administered every 24 weeks also led to a very sustained reduction in Lp(a), but we saw a little bit more variability in terms of how sustained that reduction was with that less-frequent dosing. But in all that, the 12-week dosing appeared to really achieve both a marked and sustained reduction in those Lp(a) concentrations.

In terms of the safety and tolerability, overall adverse events and serious adverse events were balanced between the olpasiran and placebo arms. The only thing of note was that patients treated with olpasiran had a higher incidence of injection site and hypersensitivity reactions. The hypersensitivity reactions were surrounding the injection site. So basically everything was a localized reaction that was related to injection sites. They were described as mild and typically resolved within 48 hours without further intervention.

So the phase III is launching in December 2022, and I think at AHA, we just really picked up on the fact there’s a tremendous amount of enthusiasm for this because there really has been an unmet need in this space. It’s now actually recommended that all adults be tested in terms of having their Lp(a) concentration measured at least once in their lifetime. But we haven’t really known what to do with those values. It identifies individuals at higher risk and yet the typical therapies that we reach for, such as statins, don’t lower Lp(a), and if anything may actually lead to a slight rise.

So people have been very eager for there to be a therapeutic that leads to this type of reduction in Lp(a) concentration. So hopefully we don’t have too much longer to wait before the phase III programs demonstrate conclusively the therapeutic value of lowering Lp(a).