Lp(a) Still Low Almost 1 Year After Last Olpasiran Injection: OCEAN(a)-DOSE

Even after stopping treatment with the novel small interfering RNA (siRNA) olpasiran (Amgen), patients experience sustained lowering of lipoprotein(a) for almost 1 year, according to new phase II data from OCEAN(a)-DOSE.

The main trial tested several doses of the subcutaneously administered drug—10 mg, 75 mg, and 225 mg every 12 weeks as well as an experimental dose of 225 mg given every 24 weeks (Q24W)—and found that each cut Lp(a), leading many to believe this would translate to reduced atherosclerotic cardiovascular disease (ASCVD) risk. Some had questioned the potential for rebound after stopping the drug, but there was also speculation that prolonged efficacy could allow patients to get their injections less often.

“It's nice to think about potential opportunities in the future about perhaps less frequent dosing,” lead author Michelle L. O’Donoghue, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. “There are other small interfering RNAs that are in development as well, and some of the early results from phase I for those therapies also suggest a very prolonged duration of action. Ultimately, it would be interesting to see both phase II and phase III results for other therapies in this space.”

The field has been moving forward fruitfully in the search for an agent to cut Lp(a) and, hopefully, reduce ASCVD events. Several RNA interference therapies that target LPA, the gene that encodes for apolipoprotein(a), an essential component needed by the liver to make Lp(a), are in development, including lepodisiran (Eli Lilly), zerlasiran (Silence Therapeutics), and pelacarsen (Novartis/Ionis Pharmaceuticals). Phase III data—needed to confirm that reducing Lp(a) indeed reduces CVD outcomes—are expected first for pelacarsen, with the Lp(a)HORIZON trial scheduled to complete next year.

“It's a very exciting time,” said Anurag Mehta, MD (Virginia Commonwealth University School of Medicine, Richmond), who was not involved in the OCEAN(a)-DOSE analysis. “Hopefully in the next 2 to 5 years, we'll have important data. This is a very underrecognized, undertested risk marker for cardiovascular disease, and hopefully with these therapeutics we can help people live longer and prevent cardiovascular disease.”

O’Donoghue agreed, saying she has never before fielded so many calls from patients and physicians alike interested in one of her studies. “There is really an unmet need in this space,” she said. “There are a lot of people who perhaps have not had their first event yet and yet have very high Lp(a) values and are currently very frustrated by the lack of available therapies to help mitigate that risk.”

Off-Treatment Results

For the OCEAN(a)-DOSE extension study, published in the August 27, 2024, issue of the Journal of the American College of Cardiology, O’Donoghue and colleagues looked at the 276 patients (98.2%) from the main trial (mean age 61.8 years; 32% women) who entered the off-treatment follow-up period and followed for a median of 86 weeks (48 weeks of treatment plus the extension phase).

The researchers found significant differences in the placebo-adjusted mean percent change in Lp(a) from baseline through 96 weeks for both the 75-mg and 225-mg doses during the off-treatment phase (all P ≤ 0.001). The differences observed for the 10-mg dose were also significant, but not at 96 weeks.

Placebo-Adjusted % Change in Lp(a) From Baseline in Off-Treatment Phase

There were no safety effects identified for any of the doses at any time point, and no deaths were reported. Notably, numerically more patients had hyperglycemia or new/worsening diabetes when treated with olpasiran compared with placebo (8.8% vs 5.6%), but the study was not powered to look at this outcome.

“We saw a great deal of uniformity across the entire population,” O’Donoghue said. “And that was true both during the on-treatment period, where we saw that there was a very uniform response at the higher dose of olpasiran in terms of suppressing Lp(a). And then similarly during the off-treatment period, the gradual return back to baseline was quite consistent among the different people in the study population.”

With time, O’Donoghue continued, the targeted patient population for drugs like olpasiran will likely expand. “Akin to the early statin trials where they initially targeted those with exceedingly high LDL-cholesterol values, these early studies for Lp(a)-lowering therapeutics are studying those patients at the very highest values,” she said. “But if we ultimately demonstrate efficacy, we'll expect that that threshold may continue to drop lower and lower with subsequent studies and also expand into broader patient populations.”

This is important given the potential for a relatively infrequently dosed drug to effect outcomes worldwide. Amgen has not yet announced the dose of olpasiran that will be used in its phase III study, but the drug will be delivered every 12 weeks.

If the outcomes trial “is positive for reducing cardiovascular risk, I think it would be a hard case to make in terms of increasing the duration between the injections,” Mehta said. “But it does hold promise based on this pharmacodynamic data.”

Future Directions

In an accompanying editorial, Jared Alexander Spitz, MD (Inova Schar Heart and Vascular, Fairfax, VA), and Anandita Agarwala, MD (Baylor Scott and White Health Heart Hospital-Plano, TX), write of the “robust” potential for benefit with drugs like olpasiran in certain racial and ethnic groups.

“It is likely that the utility of Lp(a)-specific therapies may be proportionately greater among racial and ethnic groups that have the highest prevalence of elevated Lp(a), namely, individuals of African and South Asian ancestry,” they write, adding that future trials of these drugs should include and be generalizable to these higher-risk patients.

“We eagerly await phase III cardiovascular outcome trial data to learn more about event reduction with Lp(a) lowering, appropriate treatment thresholds, and how to incorporate Lp(a) reduction into our vast array of traditional lipid-lowering and risk reduction strategies,” the editorialists say. “However, it is important to also recognize that the introduction of novel Lp(a)-reducing therapeutics presents a prime opportunity to translate the mounting discussions around health equity into action.”

Mehta agreed. “Understanding the distribution of Lp(a) in race/ethnic groups other than Caucasians will be very helpful and perhaps something which will be extremely helpful will be to understand the pharmacodynamics and the effects of these Lp(a)-lowering therapies in race/ethnic groups other than whites,” he said. “I think that will be very, very helpful as well.”