RNA therapeutics
Zerlasiran cuts Lp(a) by 80% or more at 36 weeks in phase 2, review of mechanisms and evidence (Cardiovasc Hematol Disord Drug Targets 2026)
Original title: Zerlasiran for Lipoprotein(a) Reduction: Mechanisms, Evidence, and Future Directions
Narrative review of zerlasiran, a GalNAc-conjugated siRNA silencing the LPA gene, summarising Lp(a) structure, pathophysiology and current therapeutic approaches, with a focus on published phase 1 and phase 2 trial data. In the phase 1 trial, zerlasiran achieved up to a 98% Lp(a) reduction; in the phase 2 trial, after 36 weeks of follow-up, it reduced Lp(a) by 80% or more in patients with cardiovascular disease, with modest LDL-C and apoB reductions and a favourable safety profile. The authors conclude zerlasiran is a highly targeted approach to residual cardiovascular risk, with pending phase 3 outcome-trial results needed to establish its clinical role.
Original abstract
Introduction: 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.
Methods: 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.
Results: 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.
Discussion: 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.
Conclusion: 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.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.