For patients with elevated lipoprotein(a) [Lp(a)] and established cardiovascular disease (CVD), weekly lipoprotein apheresis (LA) is the only approved treatment, but it represents a significant burden. The Lp(a)FRONTIERS APHERESIS trial investigated whether the investigational therapy pelacarsen could reduce the need for this invasive procedure.¹
Mechanism of Action
Pelacarsen is a hepatocyte-directed antisense oligonucleotide. It selectively binds to apolipoprotein(a) mRNA, which prevents the synthesis of the apo(a) protein and thereby inhibits the production of Lp(a).
Methodology
The Lp(a)FRONTIERS APHERESIS (NCT05305664) trial was a Phase 3, randomised, placebo-controlled, double-blind study conducted across 13 sites in Germany. The trial enrolled 51 adult patients with established CVD and Lp(a) levels >60mg/dL who were already undergoing weekly LA. Participants were randomised 1:1 to receive subcutaneous injections of either pelacarsen 80mg or a placebo every 4 weeks for 52 weeks. LA sessions were only performed if the Lp(a) measurement from the prior visit was >60mg/dL. The primary endpoint was the normalised rate of LA sessions performed over the 52-week period. Secondary endpoints included the time to LA avoidance (defined as ≥24 consecutive weeks without LA), total LA avoidance from week 12 to 52, and the change in Lp(a) levels from baseline.
Results
The trial met its primary endpoint. The mean normalised rate of LA sessions was significantly lower in the pelacarsen group compared to the placebo group (0.16 vs 0.93, respectively; odds ratio [OR] 0.006; 95% confidence interval [CI] 0.003, 0.013; p < 0.0001). Treatment with pelacarsen resulted in a placebo-adjusted reduction in Lp(a) of 72% from baseline at week 52 (95% CI: -79%, -61%; p < 0.0001). Furthermore, 69.2% of patients in the pelacarsen arm achieved total LA avoidance from week 12 to 52, compared to none in the placebo arm (OR 163.2; p=0.0005). The median time to achieve LA avoidance in the pelacarsen group was 6.1 weeks. Treatment-emergent adverse events were similar between groups, with the exception of injection site reactions, primarily mild erythema, which were more common with pelacarsen (38.5% vs 0%).
Interpretation
The study authors concluded, "Pelacarsen is a highly effective and well-tolerated Lp(a)-targeted therapy that substantially reduces the need for LA in patients with elevated Lp(a) and established CVD."¹ These findings suggest that pelacarsen could offer a less burdensome alternative for managing this high-risk patient population.
Next Steps
The long-term impact of pelacarsen on cardiovascular outcomes is being investigated in the ongoing Lp(a)HORIZON trial (NCT04023552).²
References
1. Parhofer KG, Julius U, Herzog AL, et al. Pelacarsen and lipoprotein(a) apheresis in secondary prevention: the Lp(a)FRONTIERS APHERESIS trial. Eur Heart J. 2026;ehag073. https://doi.org/10.1093/eurheartj/ehag073
2. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med. 2020;382:244–55. https://doi.org/10.1056/NEJMoa1905239
This study was funded by Novartis.
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