RNA therapeutics
Review updates on four RNAi drugs that cut Lp(a) by more than 80%, now entering phase 3 outcome trials (Curr Opin Cardiol 2024)
Original title: Recent updates on therapeutic targeting of lipoprotein(a) with RNA interference
This review surveys RNA interference (RNAi)-based therapies targeting Lp(a), a drug class that has already produced 16 FDA-approved medicines across other indications. RNAi approaches, antisense oligonucleotides and small interfering RNA, achieve efficient gene silencing in hepatocytes through chemical backbone modification and conjugation. Citing multiple lines of evidence that Lp(a) is causally atherogenic, and recent analyses suggesting Lp(a) is more atherogenic than LDL cholesterol, the review frames the 'Lp(a) hypothesis,' that pharmacologically lowering Lp(a) will improve cardiovascular outcomes, as the field's central open question. Four RNAi-based drugs have completed early-phase trials showing more than 80% reductions in plasma Lp(a), and phase 3 trials examining actual clinical outcomes with these agents are now underway to test that hypothesis directly.
Original abstract
Purpose Of Review: RNA interference (RNAi)-based therapies that target specific gene products have impacted clinical medicine with 16 FDA approved drugs. RNAi therapy focused on reducing plasma lipoprotein(a) [Lp(a)] levels are under evaluation.
Recent Findings: RNAi-based therapies have made significant progress over the past 2 decades and currently consist of antisense oligonucleotides (ASO) and small interfering RNA (siRNA). Chemical modification of the RNA backbone and conjugation of siRNA enables efficient gene silencing in hepatocytes allowing development of effective cholesterol lowering therapies. Multiple lines of evidence suggest a causative role for Lp(a) in atherosclerotic cardiovascular disease, and recent analyses indicate that Lp(a) is more atherogenic than low density lipoprotein- cholesterol (LDL-C). These findings have led to the 'Lp(a) hypothesis' that lowering Lp(a) may significantly improve cardiovascular outcomes. Four RNAi-based drugs have completed early phase clinical trials demonstrating >80% reduction in plasma Lp(a) levels. Phase 3 clinical trials examining clinical outcomes with these agents are currently underway.
Summary: Currently, four RNAi-based drugs have been shown to be effective in significantly lowering plasma Lp(a) levels. Clinical outcome data from phase 3 trials will evaluate the Lp(a) hypothesis.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.