CHICAGO — The remarkable and sustained reductions in lipoprotein(a) ( Lp[a]) achieved with lepodisiran (Eli Lilly) , a novel small-interfering (si)RNA molecule, in a phase 2 trial might signal a major leap forward in the management of residual cardiovascular risk if the expected therapeutic benefit is confirmed in ongoing trials.
Lepodisiran reduced Lp(a) by nearly 90% at 360 days after a single dose, and provided a similar degree of suppression over an even longer period when a second dose was administered at 180 days, according to Steven Nissen, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine.
Based on these results, “completion of ongoing phase 3 cardiovascular outcome trials is now a critical research priority to determine whether these therapies can reduce morbidity and mortality,” Nissen said. “Patients are waiting.”
An Elusive Cardiovascular Risk Factor
There are approximately 64 million people in the United States with elevated Lp(a), which is a risk marker for both cardiovascular events and all-cause mortality, Nissen said. Elevated Lp(a) has been known as a significant cardiovascular risk factor for decades, but there are no approved therapies.
In this dose-ranging study, 320 patients who were 40 years and older — average age was about 63 years — and who had a baseline Lp(a) serum concentration of at least 175 nmol/L were randomized to one of five groups, all of which involved two injections: lepodisiran doses of 16 mg, 96 mg, or 400 mg administered at baseline and again at 180 days; a lepodisiran dose of 400 mg administered at baseline and a placebo dose administered at day 180; or two placebo doses.
Efficacy and safety data for patients followed for 540 days after the first dose were presented by Nissen here at the American College of Cardiology (ACC) Scientific Session 2025, and were simultaneously published in the New England Journal of Medicine.
For the primary endpoint of Lp(a) level, the mean reduction from day 60 to day 180 was 93.9% when the two 400 mg groups were pooled. A steep fall from baseline was achieved at about day 30 in both the 400 mg groups, and that level remained unchanged for 180 days.
A dose-dependent effect was established with the lower doses of lepodisiran. After a steep and rapid decline from baseline, the mean Lp(a) nadir occurred at about day 60, when the mean reduction from baseline in the 16 mg group reached about 45% and in the 96 mg group reached about 80%. After 60 days, there was a slow upward climb, but even at day 180, the mean reduction was about 30% in the 16 mg group and nearly 70% in the 96 mg group.
Sustained, Durable Reductions in Lp(a)
In the two-dose 400 mg group, a second nadir occurred about 60 days after the second dose, at day 240, when the reduction was 96.8%; at day 360, it was 91.0%. By day 540, or 360 days after the second dose, the reduction from baseline was 74.2%.
In the single-dose 400 mg group that received placebo at day 180, Lp(a) levels climbed slowly over the subsequent 360 days but remained 53.4% below baseline 540 days after the lepodisiran dose.
Change in apolipoprotein B, a secondary endpoint, was about 12% lower than baseline at day 180 in both 400 mg groups. In the two-dose 400 mg group, the nadir was 15% lower than baseline at approximately day 240 and still 12.9% lower at day 540. In the single-dose 400 mg group, apolipoprotein B had returned nearly to baseline at day 540, and in the placebo group, apolipoprotein B climbed modestly but not significantly over the entire 540-day follow-up.
Only a handful of patients treated with lepodisiran did not achieve a major Lp(a) reduction, Nissen reported.
Only one patient — who was in the placebo group — withdrew from the study. Injection-site reactions, occurred in 11.6% of patients, were the most common adverse events associated with lepodisiran. Elevated liver enzymes, defined as more than three times the upper limit of normal, were observed in 3%-5% of patients. Both of these adverse events were mild and transient.
At baseline, the median Lp(a) was approximately 250 nmol/L. Low-density lipoprotein levels were well controlled. More than 80% of participants were White, which Nissen characterized as a study limitation, and about 40% were women.
Lepodisiran has been engineered so it is delivered to the liver, where the effect of the siRNA is to degrade messenger RNA coding for Lp(a). Although its action is a breakthrough, it has competitors, Nissen pointed out. Several strategies for blocking Lp(a), including an oral therapy called muvalaplin, now in clinical development are showing promise.
Phase 3 Outcomes Trial Has Already Launched
The phase 2 data on lepodisiran paved the way for the already launched phase 3 ACCLAIM-Lp(a) registration trial, which will test the drug’s ability to prevent major cardiovascular events and stroke. After decades of searching for a treatment for elevated Lp(a), a genetically mediated risk factor, ACCLAIM-Lp(a) is just one of three ongoing or planned phase 3 trials assessing a therapy that targets Lp(a).
“These large outcome trials will tell us the full story on the safety and efficacy of sustained reductions in Lp(a),” Nissen said.
There is excitement surrounding these new therapies, even if the promise will not be fulfilled until efficacy and safety are demonstrated, said Eugenia Gianos, MD, director of cardiovascular prevention at Northwell Health and director of the Women’s Heart Program at Lenox Hill Hospital in New York City, who was the ACC-invited discussant for the session.
“We, ourselves, and our patients are very eager to see these results and get some therapies out there for Lp(a), which is leads to devastating effects,” Gianos said.
The 540-day follow-up is reassuring, because some observational data have suggested that low levels of Lp(a) might pose risks, such as intracranial hemorrhage and new-onset diabetes, she explained, but noted that much larger studies are needed to rule out uncommon but serious risks.
Nissen said he is aware of reports about risks related to very low levels of Lp(a), but no such adverse events were observed in the lepodisiran study or, as far as he knows, in any of the ongoing randomized trials with other Lp(a)-lowering agents.
In light of this study and the other agents in clinical development, “I’m personally very optimistic,” Nissen said. Using an analogy of a soccer game with a lot of shots on goal, he said he feels confident that one or more of these promising therapies will get to the back of the net.
“The biggest problem we face is that not enough patients are being tested,” he said.
“We have got to test for this abnormality, because if we are successful with these therapies, we are going to need to know who to treat,” Nissen added.
Funding for the lepodisiran trial was provided by Eli Lilly, which is developing this therapy. Nissen reports receiving research grants from multiple pharmaceutical companies, but does not accept personal compensation from industry. Gianos reports no potential conflicts of interest.