Zerlasiran

Zerlasiran is an investigational new drug that is being evaluated to treat atherosclerotic cardiovascular disease.^[1] It is small interfering RNA (siRNA) drug candidate designed to reduce levels of lipoprotein(a), a genetically determined cardiovascular risk factor associated with atherosclerotic cardiovascular disease. Developed by Silence Therapeutics, Zerlasiran targets apolipoprotein(a) mRNA in the liver to lower circulating lipoprotein(a) concentrations. The drug is being investigated in early clinical trials as a potential therapeutic option for patients with elevated lipoprotein(a).^[1]

Zerlasiran is a double-stranded small interfering RNA (siRNA) of 19 nucleotides in length for strand. Most of the ribonucleotides are chemically modified (mainly 2′-O-methyl or 2′-fluoro-2′-deoxy sugars, with some phosphorothioate linkages) to enhance stability and reduce immunogenicity. The drug is a duplex of these modified oligonucleotides. The sense strand is 5′-conjugated with a tri-antennary N-acetyl-D-galactosamine (GalNAc) cluster attached through a multi-arm phosphodiester linker, enabling targeted delivery to the liver.^[2]

Antisense strand:^[3]

• unmodified: UAGAUGACCAAGCUUGGCA
• modified: mA (ps) fI (ps) mA fA mC fI mC fI mG fI mC fC mA fI mU fA mC (ps) fC (ps) mG

where:

• "m" denotes 2'-O-methyl modification,
• "f" denotes 2'-fluoro modification,
• “ps” denotes a phosphorothioate linkage,
• “I” is likely for inosine or another modified base,

Sense strand:^[3]

• unmodified: UUGCCAAGCUUGGUCAUCU
• modified: [M]-mC mG mG mU mA mA fU fG fG mA mC mA mG mA mG mU mU (ps) mA (ps) mU

where: "[M]" is a triantennary N-acetylgalactosamine (GalNAc) ligand attached to the 5’ end for hepatic targeting. Other abbreviations follow the sense strand modifications as above.