Olpasiran

In clinical trials, olpasiran was generally well tolerated. The most frequent adverse events were injection-site reactions, which were usually mild. No major safety signals emerged.

Olpasiran is a N-acetylgalactosamine (GalNAc), conjugated siRNA. After uptake by hepatocytes through the asialoglycoprotein receptor, the antisense strand is incorporated into the RNA-induced silencing complex (RISC), which inhibits expression of the LPA gene. This reduces apolipoprotein(a) production and lowers circulating Lp(a).

Olpasiran is a double-stranded siRNA chemically modified for stability and conjugated with GalNAc to enable hepatocyte targeting.

Olpasiran was originally developed by Arrowhead Pharmaceuticals (as ARO-LPA) and licensed to Amgen in 2016. In 2022, Arrowhead sold a portion of its royalty rights to Royalty Pharma.

In a phase 1 trial, one dose of olpasiran led to lower Lp(a) levels sustained for up to 6 months. The phase 2 OCEAN(a)-DOSE trial demonstrated dose-dependent, sustained Lp(a) lowering with acceptable tolerability. In OCEAN(a)-DOSE, olpasiran reduced Lp(a) levels by more than 95% at some doses as compared to placebo, with durable suppression persisting for up to 48 weeks after treatment discontinuation. A large phase 3 cardiovascular outcomes trial began in 2022 to determine whether Lp(a) reduction with olpasiran decreases events in patients with established ASCVD and a history of cardiovascular events.