From GalNAc-conjugated injectables to the oral inhibitor muvalaplin, review surveys the Lp(a)-lowering pipeline and calls for an isoform-independent assay standard (Pharmaceuticals (Basel) 2025)

Original title: Lp(a)-Lowering Agents in Development: A New Era in Tackling the Burden of Cardiovascular Risk?

Pharmaceuticals (Basel) · 19 May 2025 · 6

Katsiki N, Vrablik M, Banach M, Gouni-Berthold I

This narrative review by Katsiki, Vrablik, Banach and Gouni-Berthold surveys Lp(a)-targeted drugs in development, noting that no Lp(a)-lowering therapy is currently approved and that Lp(a) is presently used mainly to refine cardiovascular risk, particularly at borderline risk or with a family history of premature coronary disease. It covers GalNAc-conjugated antisense oligonucleotide and siRNA agents that inhibit hepatic apo(a) synthesis, including the injectable pelacarsen, olpasiran, zerlasiran and lepodisiran, and highlights muvalaplin as a distinct oral small-molecule inhibitor of Lp(a) formation with potential practical advantages. The review summarises available phase 1 and 2 efficacy and safety data for these agents, their effects on other lipid parameters, and briefly previews ongoing phase 3 cardiovascular outcomes trials for pelacarsen, olpasiran and lepodisiran. The authors call for evidence-based guidelines on Lp(a) reduction once phase 3 results mature, and for establishing an ideal, apo(a)-isoform-independent Lp(a) quantification method reported in molar units.

Original abstract

Lipoprotein (a) [Lp(a)] has been recognized as an independent, inherited, causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, thus representing a major target of residual CV risk. Currently, no drug has been officially approved for lowering Lp(a) levels, and in clinical practice, Lp(a) is mainly used to (re)define CV risk, particularly in individuals at borderline CV risk and people with a family history of premature coronary heart disease, according to various guidelines. Specific Lp(a)-targeted antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) agents have been developed to produce substantial Lp(a) reductions via the inhibition of apo(a) synthesis in the liver. These drugs are conjugated to N-acetylgalactosamine (GalNAc) to ensure their binding to asialoglycoproteins, which are specifically expressed on the surface of the hepatocytes. Such drugs include pelacarsen (an injectable ASO) and olpasiran, zerlasiran, and lepodisiran (injectable siRNA agents). Muvalaplin represents another therapeutic option to lower Lp(a) levels, since it is an oral selective small molecule inhibitor of Lp(a) formation, thus potentially exerting certain advantages in terms of its clinical use. The present narrative review summarizes the available clinical data on the efficacy and safety of these investigational Lp(a)-lowering therapies, as reported in phase 1 and 2 trials. The effects of these drugs on other [aside from Lp(a)] lipid parameters are also discussed. The phase 3 CV trial outcomes are ongoing for some of these agents (i.e., pelacarsen, olpasiran, and lepodisiran) and are briefly mentioned. Overall, there is an urgent need for evidence-based guidelines on Lp(a) reduction in daily clinical practice, following the results of the phase 3 CV trials, as well as for establishing the ideal Lp(a) quantification method (i.e., using an apo(a) isoform-independent assay with appropriate calibrators, reporting the Lp(a) level in molar units).

Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.