Antisense oligonucleotide targeting apolipoprotein(a) Treatment of lipoprotein disorders Treatment of cardiovascular diseases

Elevated levels of lipoprotein(a) [Lp(a)] are a prevalent and causative risk factor for atherosclerotic cardiovascular disease (ASCVD), but effective pharmacologic strategies for Lp(a) lowering are needed. Antisense oligonucleotides (ASOs) are effective for gene silencing and reducing production of unwanted proteins. Pelacarsen, a subcutaneously administered third-generation ASO directed against apolipoprotein(a) [apo(a)], prevents translation of and induces degradation of apo(a) messenger ribonucleic acid (mRNA). Pelacarsen has multiple side-chain modifications, including conjugation with N-acetylgalactosamine (GalNAc), which increases drug potency, half-life and drug tolerance. Pelacarsen significantly reduces Lp(a) concentrations by up to 80-90%, which may allow many patients to achieve normal Lp(a) levels. Pelacarsen has a good safety profile, bypassing toxicities associated with second-generation ASOs. The medical community awaits the results of the phase III Lp(a)HORIZON trial evaluating use of pelacarsen in patients with elevated Lp(a) and established ASCVD, which will provide the first definitive evidence of whether Lp(a) lowering reduces ASCVD risk.