Small interfering RNAs (siRNAs) are ‘gene silencing’ agents that consist of double stranded sequences of RNA, typically 20-25 base pairs in length.1 An siRNA is composed of a guide strand complementary to the target messenger RNA (mRNA) of the gene to be silenced, and a passenger strand. Inside the cell, the siRNA is incorporated into the RNA-induced silencing complex (RISC).1 The passenger strand is removed and the activated complex breaks down the target mRNA when the guide strand binds to the target sequence.1
siRNAs in development to reduce Lp(a) target LPA mRNA. Like ASOs, siRNAs can be directed to hepatocytes in the liver, where Lp(a) particles are mainly produced, through conjugation of the siRNA with an N-acetylgalactosamine (GalNac) moiety. This binds to the asialoglycoprotein receptor on the hepatocyte surface, facilitating entry of the siRNA into the cell.
Lepodisiran (formerly LY3819469) is a GalNac siRNA targeting LPA. In a Phase 1 study in adults with elevated Lp(a), lepodisiran in doses ≥32 mg reduced Lp(a) by ≥90%, with this level of reduction sustained for approximately 11 months.3
Olpasiran (formerly AMG 890) is a GalNac siRNA targeting LPA. In a Phase 1 study in adults with elevated Lp(a), olpasiran in doses ≥9 mg reduced Lp(a) by >90% with effects persisting for three to six months.2
Zerlasiran (formerly SLN260) is a GalNac siRNA targeting LPA. In a Phase 1 study in adults with elevated Lp(a), zerlasiran in doses ≥300 mg reduced Lp(a) by ≥90% with efficacy persisting for more than 20 weeks.4
siRNAs in development to reduce Lp(a) target LPA mRNA. Like ASOs, siRNAs can be directed to hepatocytes in the liver, where Lp(a) particles are mainly produced, through conjugation of the siRNA with an N-acetylgalactosamine (GalNac) moiety. This binds to the asialoglycoprotein receptor on the hepatocyte surface, facilitating entry of the siRNA into the cell.
Lepodisiran (formerly LY3819469) is a GalNac siRNA targeting LPA. In a Phase 1 study in adults with elevated Lp(a), lepodisiran in doses ≥32 mg reduced Lp(a) by ≥90%, with this level of reduction sustained for approximately 11 months.3
Olpasiran (formerly AMG 890) is a GalNac siRNA targeting LPA. In a Phase 1 study in adults with elevated Lp(a), olpasiran in doses ≥9 mg reduced Lp(a) by >90% with effects persisting for three to six months.2
Zerlasiran (formerly SLN260) is a GalNac siRNA targeting LPA. In a Phase 1 study in adults with elevated Lp(a), zerlasiran in doses ≥300 mg reduced Lp(a) by ≥90% with efficacy persisting for more than 20 weeks.4
View References
- Thau H, Neuber S, Emmert MY et al. Targeting Lipoprotein(a): Can RNA Therapeutics Provide the Next Step in the Prevention of Cardiovascular Disease? Cardiol Ther. 2024 Mar;13(1):39-67.
- O'Donoghue ML, G López JA, Knusel B et al. Study design and rationale for the Olpasiran trials of Cardiovascular Events And lipoproteiN(a) reduction-DOSE finding study (OCEAN(a)-DOSE). Am Heart J. 2022 Sep;251:61-69.
- Nissen SE, Linnebjerg H, Shen X et al. Lepodisiran, an Extended-Duration Short Interfering RNA Targeting Lipoprotein(a): A Randomized Dose-Ascending Clinical Trial. JAMA. 2023 Dec 5;330(21):2075-2083
- Nissen SE, Wolski K, Balog C et al. Single ascending dose study of a short interfering RNA targeting lipoprotein(a) production in individuals with elevated plasma lipoprotein(a) levels. JAMA. 2022 May 3;327(17):1679-1687.
