Zerlasiran for Lipoprotein(a) Reduction: Mechanisms, Evidence, and Future Directions

Lipoprotein(a) [Lp(a)] is a genetically determined, independent risk factor for atherosclerotic cardiovascular disease (ASCVD). While it contributes significantly to residual cardiovascular risk, it remains under-recognized in clinical practice. In recent years, several novel drugs have been developed to lower Lp(a) levels, with multiple therapies currently under investigation.

This narrative review provides a summary of the structure and pathophysiological role of Lp(a) and current therapeutic approaches for its reduction. The primary focus is a critical analysis of published Phase 1 and Phase 2 clinical trial data on Zerlasiran, a GalNAc-conjugated siRNA developed to silence the LPA gene.

Zerlasiran has shown promising results in early clinical trials. In the Phase 1 trial, it achieved up to a 98% reduction in Lp(a) levels. In the Phase 2 trial, after a 36-week follow-up, Zerlasiran reduced Lp(a) levels by 80% or more in patients with cardiovascular disease, along with modest reductions in LDL-C and ApoB, and demonstrated a favorable safety profile.

These findings suggest that Zerlasiran and similar siRNA therapies may address a significant unmet need in cardiovascular prevention by targeting a key component of residual risk. However, the long-term impact of Lp(a) lowering on clinical outcomes, such as Major Adverse Cardiovascular Events (MACE), remains to be determined.

Zerlasiran represents a novel and highly targeted approach to managing elevated Lp(a), with the potential to shift future ASCVD prevention strategies. Pending Phase 3 trial results will be critical in establishing its role in clinical practice.