Givosiran: Mechanism of Action and Chemical Properties

Givosiran: Mechanism of Action and Chemical Properties

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The full Prescribing Information for GIVLAARI® (givosiran) is provided here. Alnylam Pharmaceuticals does not recommend the use of its products in any manner that is inconsistent with the approved Prescribing Information. This resource may contain information that is not in the approved Prescribing Information.

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INDEX

Label Information – RNA Interference – Chemical Properties – Abbreviations – References

givlaari prescribing information – Relevant content

The CLINICAL PHARMACOLOGY section provides the following information1:

Mechanism of Action

Givosiran is a double-stranded small interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA. This leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of AHP.

The DESCRIPTION section provides the following information1:

GIVLAARI is an aminolevulinate synthase 1-directed small interfering RNA (siRNA), covalently linked to a ligand containing three N-acetylgalactosamine (GalNAc) residues to enable delivery of the siRNA to hepatocytes.

RNA INterference

RNAi is a natural endogenous intracellular catalytic mechanism that potentially enables the specific and potent silencing of any gene by targeting mRNA for degradation, hence preventing the expression of proteins and their function in disease.3,4 RNAi uses siRNAs for the control of gene expression. The siRNAs are loaded onto the cytoplasmic RISC. The RISC cleaves the specific mRNA target through AGO2, the catalytic component of the RISC, and the cleaved mRNA is then degraded, thus preventing the synthesis of the protein encoded by that mRNA.5–7

Chemical Properties

Givosiran consists of chemically modified siRNA containing a combination of 2’ F and 2’ O-methyl nucleotides, conjugated to a triantennary GalNAc ligand to facilitate delivery of the siRNA to the liver.2

The two single strands that form the double stranded RNA molecule are A-122230, the sense strand, and A122227, the antisense strand, creating 21 complementary base pairs (Figure 1).1,2

Figure 1. The Structural Formulas of the Givosiran Drug Substance in its Sodium Form, and the Ligand (L96).1,a

Abbreviations

Af = adenine 2'-F ribonucleoside; AGO2 = argonaute RISC catalytic component 2; AHP   = acute hepatic porphyria; ALA = 5’‑aminolevulinic acid; ALAS1 = 5’-aminolevulinic acid synthase 1; Am = adenine 2'-OMe ribonucleoside; Cf = cytosine 2'‑F ribonucleoside; Cm = cytosine 2'-OMe ribonucleoside; GalNAc = N-acetyl galactosamine; Gf = guanine 2'-F ribonucleoside; Gm = guanine 2'-OMe ribonucleoside; L96 = triantennary GalNAc (N-acetylgalactosamine); mRNA = messenger RNA; PBG = porphobilinogen; RISC = RNA-induced silencing complex; RNAi = RNA interference; siRNA = small interfering ribonucleic acid; TTR = transthyretin; Uf = uracil 2'-F ribonucleoside; Um = uracil 2'-OMe ribonucleoside.

Updated 7 January 2025

References

1.  GIVLAARI (givosiran) Prescribing Information. Cambridge, MA: Alnylam Pharmaceuticals, Inc.

2.  Givlaari : EPAR – Public assessment report. European Medicines Agency. Published March 09, 2020. Accessed January 7, 2025. https://www.ema.europa.eu/documents/assessment-report/givlaari-epar-public-assessment-report_en.pdf.

3.  Elbashir S, Harborth J, Lendeckel W, et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001;411(6836):494-498. doi:10.1038/35078107

4.  Fire A, Xu S, Montgomery M, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391(6669):806-811. doi:10.1038/35888

5.  Deleavey GF, Damha MJ. Designing Chemically Modified Oligonucleotides for Targeted Gene Silencing. Chem Biol. 2012;19(8):937-954. doi:10.1016/j.chembiol.2012.07.011

6.  Niemietz C, Chandhok G, Schmidt H. Therapeutic Oligonucleotides Targeting Liver Disease: TTR Amyloidosis. Molecules. 2015;20(10):17944-17975. doi:10.3390/molecules201017944

7.  Agrawal N, Dasaradhi P, Mohmmed A, et al. RNA Interference: Biology, Mechanism, and Applications. Microbiol Mol Biol Rev. 2003;67(4):657-685. doi:10.1128/MMBR.67.4.657-685.2003