Assessing the clinical development of zerlasiran, a small-interfering RNA for elevated lipoprotein(a)

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.

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.

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.