Givosiran sodium is a subcutaneously administered siRNA targeting hepatic ALAS1 mRNA [1]. Givosiran sodium is conjugated to a trivalent N-acetylgalactosamine ligand, which can be specifically delivered to hepatocytes, resulting in downregulation of ALAS1 mRNA and preventing accumulation of neurotoxic δ-aminolevulinic acid and porphobilinogen (PBG) levels that are associated with acute porphyria attacks [2]. Givosiran sodium has been widely used to rapidly and sustainably reduce ALAS1 mRNA, decrease heme precursor levels, and lower the rate of acute attacks [3].
In vivo, Givosiran sodium treatment via subcutaneous injection at a dose of 3mg/kg, twice a week for 3 weeks, significantly reduced the liver ALAS1 mRNA level and the accumulation of 5-aminolevulinic acid (ALA) and PBG in the urine of the acute intermittent porphyria (AIP) mouse model [4].
References:
[1] Balwani M, Sardh E, Ventura P, et al. Phase 3 trial of RNAi therapeutic Givosiran sodium for acute intermittent porphyria[J]. New England journal of medicine, 2020, 382(24): 2289-2301.
[2] Scott L J. Givosiran sodium: first approval[J]. Drugs, 2020, 80(3): 335-339.
[3] Sardh E, Harper P. RNAi therapy with Givosiran sodium significantly reduces attack rates in acute intermittent porphyria[J]. Journal of Internal Medicine, 2022, 291(5): 593-610.
[4] Chan A, Liebow A, Yasuda M, et al. Preclinical development of a subcutaneous ALAS1 RNAi therapeutic for treatment of hepatic porphyrias using circulating RNA quantification[J]. Molecular Therapy Nucleic Acids, 2015, 4.