Two new therapies targeting lipoprotein(a) (Lp(a)) have demonstrated significant efficacy in early-phase studies. One is a small interfering RNA (siRNA) drug, and the other is an oral agent, both reducing Lp(a) by approximately 80% or more in patients with atherosclerotic cardiovascular disease (ASCVD).
In one study, the siRNA therapy lowered Lp(a) by as much as 85% over 36 weeks. The other trial showed that the oral agent reduced Lp(a) by more than 85% using advanced assays.
These therapies address a critical gap, as no approved treatments currently exist specifically to lower Lp(a) levels, which are linked to cardiovascular diseases like ASCVD and calcific aortic stenosis.
Traditional treatments like statins and ezetimibe do not lower Lp(a) and can even increase its levels slightly. Additionally, lifestyle and dietary changes have minimal impact on Lp(a).
KRAKEN Trial: Oral Agent Shows Promise
The KRAKEN trial tested an oral agent in 233 patients with ASCVD, diabetes, or familial hypercholesterolemia. Participants received varying doses or placebo, and most were already on statins and antithrombotic agents.
At the highest dose, the oral agent reduced Lp(a) by 85.7% over 12 weeks. A significant proportion of patients achieved Lp(a) levels considered safe, with reductions also noted in oxidized phospholipids, which contribute to atherosclerosis.
The oral therapy showed no significant safety concerns, with no increases in adverse events or liver enzyme abnormalities.
ALPACAR-360: siRNA Therapy Results
The ALPACAR-360 study evaluated the siRNA therapy in 178 patients with ASCVD and elevated Lp(a). Patients received different doses over 36 weeks.
The siRNA therapy achieved 85.6% reductions in Lp(a) at the highest dose. It also reduced LDL cholesterol by 25% to 32% and apoB by 10% to 15%.
Most side effects were mild, including headache, nasopharyngitis, and injection-site reactions, none of which led to study withdrawal.
Unanswered Questions and Future Directions
It remains unknown whether lowering Lp(a) will translate to a reduced risk of cardiovascular events. Ongoing trials, including large cardiovascular outcomes studies, are expected to provide answers between 2025 and 2029.
Future research will also need to address questions such as what constitutes “too high” Lp(a) levels and when intervention should occur.
Another challenge is ensuring Lp(a) testing is accessible and covered by payers, as it is currently not included in many health systems' standard screenings.
Key Takeaways
- Two new therapies—oral and siRNA-based—lowered Lp(a) by 80% or more in early-phase trials.
- These treatments fill a critical gap, as no approved Lp(a)-lowering therapies currently exist.
- Both therapies showed strong safety profiles with minimal side effects.
- Ongoing research will clarify whether lowering Lp(a) reduces cardiovascular events.
- Advocating for universal Lp(a) testing is essential for risk stratification and prevention.
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