The mechanism of action of givosiran. Givosiran is an RNAi medication that inhibits ALAS1 in the liver. Givosiran is conjugated to N-acetylgalactosamine (GalNac), which mediates its targeting to hepatocytes. The ASGPR transmembrane receptors on hepatocytes have high affinity and specificity for GalNac. After binding to ASGPR receptors, givosiran is brought into endolysosomes, where the GalNac ligand is rapidly degraded. Givosiran's double-stranded ALAS1 small interfering RNA (ALAS1-siRNA) molecule is released into the cytosol, where it is cleaved by the enzyme dicer into slightly shorter double-stranded fragments of approximately 20 base pairs and separated into single-stranded RNAs, a passenger (sense) strand and guide (antisense) strand. The passenger strand is degraded, and the guide strand binds to cellular ALAS1-mRNA and is incorporated into the RNA-induced silencing complex (RISC). RISC then cleaves the new double-stranded RNA, resulting in a decrease in the amount of ALAS1 enzyme. Professional illustration by Somersault18:24.