Lepodisiran Reduces Lipoprotein(a) Levels Safely in Phase 1 Data, Paving Way for Further Study


Eli Lilly’s small interfering RNA therapy showed significant serum reductions with a single dose while remaining well-tolerated. A larger phase 2 study is currently ongoing.

Steve Nissen, MD, chief academic officer of the Heart Vascular & Thoracic Institute at Cleveland Clinic

Steve Nissen, MD

Data from a phase 1 study (NCT04914546) of lepodisiran (Eli Lilly) in patients with elevated lipoprotein(a) levels that were presented at the American Heart Association Scientific Sessions, held November 11-13, 2023, in Philadelphia, Pennsylvania, suggest that the therapy is well-tolerated and produces dose-dependent reductions of serum lipoprotein(a) levels for long durations. Ultimately, the investigators noted that these data support further study of the small interfering RNA therapeutic.1,2

The effort, led and presented at the meeting by Steve Nissen, MD, chief academic officer of the Heart Vascular & Thoracic Institute at Cleveland Clinic, showed that the group treated with a 608-mg dose (n = 6) reported a 97% reduction (IQR, –98 to –96) in lipoprotein(a) levels, with a median reduction of 94% at day 337. Among the several other doses assessed, there were reductions of 41% (IQR, −47 to −20) in the 4-mg lepodisiran group (n = 6), 59% (IQR, –66 to –53) in the 12-mg dose group (n = 6), 76% (IQR, –76 to –75) in the 32-mg dose group (n = 5), 90% (IQR, –94 to –85) in the 96-mg dose group (n = 6), and 96% (IQR, –98 to –95) in the 304-mg dose group (n = 6). Comparatively, the placebo group (n = 11) reported a maximal median reduction from baseline of 5% (IQR, −16 to 11).

“It's like nothing the world has ever seen. At the 608-mg dose, levels of lipoprotein(a) dropped to below the lower limit of quantitation for their standard Roche assay, and remained unmeasurable for the next 281 days,” Nissen said in an interview with CGTLive’s sister publication, HCPLive Cardiology.

As for safety, only 1 single serious adverse event (AE) occurred in the 4-mg dose group—a facial injury after a fall from a bicycle, occurring 141 days post injection of lepodisiran. All other investigator-reported AEs were deemed uncommon and similar across all groups. Injection site reactions that occurred included pain at the injection site, reported in most of the groups (including the placebo group). Most injection site reactions resolved prior to discharge from the clinical research unit, though erythema persisted to day 8 for 1 participant in the placebo group.1

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Additionally, 2 patients had elevated levels of aminotransaminase (>3 times the upper limit of normal [ULN])—1 had elevated alanine aminotransferase and aspartate aminotransferase, and 1 had elevated alanine aminotransferase. Another 3 individuals treated with lepodisiran had creatine kinase levels that were greater than 5 times ULN. All of these were considered transient and returned to normal at the next visit.

“Despite the strong evidence of the importance of elevated lipoprotein(a) as a risk factor, effective treatment has been elusive. Lifestyle modifications that are useful for the treatment of most other lipid disorders have little or no effect on lipoprotein(a) concentrations,” Nissen et al wrote, noting that the conventional therapies—statins and fibrates—lack evidence of an ability to lower lipoprotein(a) levels, and other approaches result in lackluster reductions. Apheresis, they explained, does substantially lower levels, but is cumbersome and not widely applicable. “In the current trial, even at the highest dose, lepodisiran was no longer present in plasma after 48 hours. However, the effect of lepodisiran on lipoprotein(a) concentration persisted for much longer, which may allow administration of the drug once or twice yearly to achieve a high degree of lipoprotein(a)-lowering efficacy,” they wrote.

Key Takeaways

  1. Lepodisiran Reduces Lipoprotein(a): In a phase 1 study, lepodisiran demonstrated dose-dependent reductions in lipoprotein(a) levels for extended durations, supporting further investigation of the small interfering RNA therapeutic.
  2. Dose-Dependent Efficacy: The 608-mg dose resulted in a 97% reduction in lipoprotein(a) levels, showing unprecedented efficacy. Safety profiles were favorable, supporting potential long-term use.
  3. Promising Cardiovascular Risk Factor Treatment: Lepodisiran, if proven safe and effective in larger trials, could address a challenging cardiovascular risk factor—elevated lipoprotein(a)—with a unique mechanism, potentially offering a meaningful therapeutic option.

The phase 1 trial enrolled 48 participants without cardiovascular disease and with lipoprotein(a) concentrations of 75 nmol/L or greater, or 30 mg/dL or greater. A larger phase 2 study is currently underway (NCT05565742) with an expected enrollment of 254 patients, which Nissen and colleagues noted might offer additional data regarding safety, tolerability, and rarer adverse events.

“If further trials show that this medication—lepodisiran—is safe and can reduce heart attacks and strokes, it would be good news for patients because it eliminates a risk factor we’ve been unable to treat,” Nissen said in a statement.2 “How do you beat a risk factor that’s largely genetic? One highly effective approach is to interfere with the gene, and that’s what lepodisiran and other new therapies are designed to do.”

A key limitation Nissen et al pointed out was that the lipoprotein(a) level required for participants in the study was only moderately elevated—which they described as “the upper limit of normal for most laboratories.” They wrote, “Although there is debate regarding the magnitude of lipoprotein(a) lowering to lower cardiovascular risk, those with higher plasma concentrations will likely derive the most benefit,” adding that the effects of the treatment in those with cardiovascular disease are also still unclear.

1. Nissen SE, Linnebjerg H, Shen X, et al. Lepodisiran, an Extended-Duration Short Interfering RNA Targeting Lipoprotein(a): A Randomized Dose-Ascending Clinical Trial. JAMA. Published online November 12, 2023. doi:10.1001/jama.2023.21835
2. One dose of experimental therapy reduced lipoprotein(a) more than 94% for nearly a year. AHA. News release. November 12, 2023. Accessed November 17, 2023. https://newsroom.heart.org/news/one-dose-of-experimental-therapy-reduced-lipoprotein-a-more-than-94-for-nearly-a-year
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