Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease

This phase 1 dose-escalation trial assessed the safety, pharmacodynamics, and efficacy of olpasiran, a small interfering RNA (siRNA) targeting hepatic production of apolipoprotein(a) in patients with established atherosclerotic cardiovascular disease and elevated lipoprotein(a) [Lp(a)] levels. Among 64 participants, subcutaneous olpasiran was administered in doses ranging from 3 mg to 225 mg every 12 weeks. All dose levels resulted in substantial reductions in Lp(a), with higher doses achieving >95% mean reduction from baseline sustained through dosing intervals. Olpasiran was generally well-tolerated, with adverse events primarily mild or unrelated to treatment. Injection-site reactions were infrequent and transient; no serious hepatotoxicity, renal toxicity, or thrombocytopenia occurred. The trial demonstrated that sustained Lp(a) lowering via RNA interference is feasible, supporting olpasiran’s progression to phase 2 studies. These findings highlight the potential of siRNA-based therapies to address genetically driven cardiovascular risk associated with elevated Lp(a), an independent contributor to atherothrombosis not modifiable by statins.

This phase 1 dose-escalation trial assessed the safety, pharmacodynamics, and efficacy of olpasiran, a small interfering RNA (siRNA) targeting hepatic production of apolipoprotein(a) in patients with established atherosclerotic cardiovascular disease and elevated lipoprotein(a) [Lp(a)] levels. Among 64 participants, subcutaneous olpasiran was administered in doses ranging from 3 mg to 225 mg every 12 weeks. All dose levels resulted in substantial reductions in Lp(a), with higher doses achieving >95% mean reduction from baseline sustained through dosing intervals. Olpasiran was generally well-tolerated, with adverse events primarily mild or unrelated to treatment. Injection-site reactions were infrequent and transient; no serious hepatotoxicity, renal toxicity, or thrombocytopenia occurred. The trial demonstrated that sustained Lp(a) lowering via RNA interference is feasible, supporting olpasiran’s progression to phase 2 studies. These findings highlight the potential of siRNA-based therapies to address genetically driven cardiovascular risk associated with elevated Lp(a), an independent contributor to atherothrombosis not modifiable by statins.