RNA therapeutics
Zerlasiran's long half-life and infrequent dosing make it a promising siRNA candidate for lowering Lp(a), phase 2 review finds, with phase 3 outcomes still to come (Expert Opin Investig Drugs 2025)
Original title: Assessing the clinical development of zerlasiran, a small-interfering RNA for elevated lipoprotein(a)
This review by Tang, Hooper and Burnett examines the clinical development of zerlasiran, a GalNAc-conjugated small interfering RNA that lowers Lp(a) by targeting hepatic apolipoprotein(a) synthesis and the subsequent assembly of the Lp(a) particle. It covers zerlasiran's pharmacodynamics, pharmacokinetics and metabolism, noting the drug shows efficacy comparable to other Lp(a)-lowering therapies at the phase 2 stage, alongside a favourable safety and tolerability profile. Its long half-life and infrequent dosing, together with potentially lower cost, distinguish it as a promising candidate in the field of Lp(a)-lowering agents that currently has no approved therapy. The authors caution that the phase 3 cardiovascular outcomes study has not yet commenced, so long-term data on major adverse cardiovascular events and safety across diverse populations remain to be established.
Original abstract
Introduction: Lipoprotein(a) [Lp(a)] is an independent, inherited risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Lp(a) is an LDL-like particle containing apoB-100 and apo(a). Lifestyle changes and statin therapy lower LDL-cholesterol and apoB, but do not reduce Lp(a), whereas PCSK9 inhibitors exert a modest effect. There are currently no approved Lp(a)-lowering drugs, although several are at various phases of clinical development.
Areas Covered: We discuss the role of Lp(a) as a therapeutic target, describe the development, pharmacodynamics, pharmacokinetics, and metabolism of zerlasiran, a small interfering RNA (siRNA) targeting Lp(a), and report the findings of recent clinical trials.
Expert Opinion: The GalNAc-conjugated siRNA zerlasiran reduces Lp(a) by targeting hepatic apo(a) synthesis and subsequent assembly of Lp(a), with comparable efficacy to other Lp(a)-lowering therapies in phase II development. Its long half-life, infrequent dosing, and potentially lower cost, together with its favorable safety and tolerability profile, make zerlasiran a promising candidate. However, long-term studies are needed to assess its impact on major adverse cardiovascular events and safety in diverse patient populations, and across different clinical settings. The phase III cardiovascular outcome study has not commenced.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.