Givosiran is a small interfering ribonucleic acid agent that was recently 
approved in the United States for the treatment of acute hepatic porphyria 
(AHP). This phase I study evaluated the safety, pharmacokinetic, and 
pharmacodynamic profile of subcutaneously (SC) administered givosiran in 
patients with acute intermittent porphyria, the most common AHP type. Givosiran 
was rapidly absorbed from the SC injection site with peak plasma concentrations 
achieved within 0.5-5 hours followed by elimination with a short half-life of 
4-10 hours. Plasma exposures of AS(N-1)3' givosiran, an active metabolite with 
equal potency as givosiran, was 35%-75%. Givosiran treatment resulted in a rapid 
and dose-dependent reduction in urinary aminolevulinic acid (ALA) and 
porphobilinogen (PBG) towards the upper limit of normal (ULN) in AHP patients. 
Greater and more sustained reductions in ALA and PBG were achieved with once 
monthly dosing compared with once quarterly dosing. After monthly dosing, trough 
ALA levels were reduced to below the ULN, approximately 95% reduction from 
baseline, at both the 2.5 and 5.0 mg/kg doses.