BACKGROUND: Up-regulation of hepatic delta-aminolevulinic acid synthase 1 
(ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and 
porphobilinogen, is central to the pathogenesis of acute attacks and chronic 
symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, 
inhibits ALAS1 expression.
METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly 
assigned symptomatic patients with acute hepatic porphyria to receive either 
subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly 
for 6 months. The primary end point was the annualized rate of composite 
porphyria attacks among patients with acute intermittent porphyria, the most 
common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted 
in hospitalization, an urgent health care visit, or intravenous administration 
of hemin at home.) Key secondary end points were levels of ALA and 
porphobilinogen and the annualized attack rate among patients with acute hepatic 
porphyria, along with hemin use and daily worst pain scores in patients with 
acute intermittent porphyria.
RESULTS: A total of 94 patients underwent randomization (48 in the givosiran 
group and 46 in the placebo group). Among the 89 patients with acute 
intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran 
group and 12.5 in the placebo group, representing a 74% lower rate in the 
givosiran group (P<0.001); the results were similar among the 94 patients with 
acute hepatic porphyria. Among the patients with acute intermittent porphyria, 
givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of 
hemin use, and better daily scores for pain than placebo. Key adverse events 
that were observed more frequently in the givosiran group were elevations in 
serum aminotransferase levels, changes in serum creatinine levels and the 
estimated glomerular filtration rate, and injection-site reactions.
CONCLUSIONS: Among patients with acute intermittent porphyria, those who 
received givosiran had a significantly lower rate of porphyria attacks and 
better results for multiple other disease manifestations than those who received 
placebo. The increased efficacy was accompanied by a higher frequency of hepatic 
and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION 
ClinicalTrials.gov number, NCT03338816.).