Givosiran is a synthetic, chemically stabilized small interfering RNA (siRNA) therapeutic designed to selectively reduce expression of aminolevulinate synthase 1 (ALAS1) in hepatocytes. It is conjugated to a triantennary N-acetylgalactosamine (GalNAc) ligand, which facilitates targeted uptake into liver cells through the asialoglycoprotein receptor.
Givosiran is marketed as GIVLAARI and is indicated for the treatment of adults with acute hepatic porphyria (AHP). The FDA approved GIVLAARI on November 20, 2019.
Unlike conventional small-molecule APIs, Givosiran is a large, double-stranded oligonucleotide conjugate. The drug substance is supplied in its sodium form. FDA reports a molecular formula of C524H651F16N173Na43O316P43S6 and molecular weight of 17,245.56 Da for givosiran sodium. The corresponding free-acid form has a molecular weight of 16,300.34 Da.
Givosiran uses RNA interference (RNAi) to reduce ALAS1 mRNA in hepatocytes. This decreases production of the neurotoxic heme-pathway intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), which are associated with manifestations of acute hepatic porphyria.
| Parameter | Specification |
|---|---|
| Appearance | White to off-white crystalline powder |
| Identification | IR & HPLC compliant |
| Assay (HPLC) | 98.0% – 102.0% |
| Loss on Drying | NMT 1.0% |
| Residue on Ignition | NMT 0.5% |
| Heavy Metals | NMT 20 ppm |
| Individual Impurity | NMT 0.5% |
| Total Impurities | NMT 2.0% |
| Water Content | NMT 1.0% |