In November 2019 givosiran became the second small interfering RNA (siRNA)-based 
drug to receive US Food and Drug Administration (FDA) approval, it has been 
developed for the treatment of acute intermittent porphyria (AIP), a disorder 
characterized by life-threatening acute neurovisceral attacks. The porphyrias 
are a group of disorders in which enzymatic deficiencies in heme production lead 
to toxic accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen 
(PBG), which are involved in the neurovisceral attacks. Givosiran acts as a 
conventional siRNA to trigger RNA interference (RNAi)-mediated gene silencing on 
delta-ALA synthase 1 (ALAS1), thus returning ALA and PBG metabolites to the 
physiological level to attenuate further neurotoxicity. Givosiran makes use of a 
new hepatic-delivery system that conjugates three GalNac (N-acetylgalactosamine) 
molecules to the siRNA passenger strand. GalNac binds to the liver 
asialoglycoprotein receptor, favoring the internalization of these 
GalNac-conjugated siRNAs into the hepatic cells. In a phase I study, 
subcutaneous monthly administration of givosiran 2.5 mg/kg reduced > 90% of ALA 
and PBG content. This siRNA is being analyzed in ENVISION (NCT03338816), a phase 
III, multicenter, placebo-controlled randomized controlled trial. In preliminary 
results, givosiran achieved clinical endpoints for AIP, reducing urinary ALA 
levels, and presented a safety profile that enabled further drug development. 
The clinical performance of givosiran revealed that suppression of ALAS1 by 
GalNac-decorated siRNAs represents an additional approach for the treatment of 
patients with AIP that manifests recurrent acute neurovisceral attacks.