BACKGROUND: Induction of delta aminolevulinic acid synthase 1 ( ALAS1) gene 
expression and accumulation of neurotoxic intermediates result in neurovisceral 
attacks and disease manifestations in patients with acute intermittent 
porphyria, a rare inherited disease of heme biosynthesis. Givosiran is an 
investigational RNA interference therapeutic agent that inhibits hepatic ALAS1 
synthesis.
METHODS: We conducted a phase 1 trial of givosiran in patients with acute 
intermittent porphyria. In part A of the trial, patients without recent 
porphyria attacks (i.e., no attacks in the 6 months before baseline) were 
randomly assigned to receive a single subcutaneous injection of one of five 
ascending doses of givosiran (0.035, 0.10, 0.35, 1.0, or 2.5 mg per kilogram of 
body weight) or placebo. In part B, patients without recent attacks were 
randomly assigned to receive once-monthly injections of one of two doses of 
givosiran (0.35 or 1.0 mg per kilogram) or placebo (total of two injections 28 
days apart). In part C, patients who had recurrent attacks were randomly 
assigned to receive injections of one of two doses of givosiran (2.5 or 5.0 mg 
per kilogram) or placebo once monthly (total of four injections) or once 
quarterly (total of two injections) during a 12-week period, starting on day 0. 
Safety, pharmacokinetic, pharmacodynamic, and exploratory efficacy outcomes were 
evaluated.
RESULTS: A total of 23 patients in parts A and B and 17 patients in part C 
underwent randomization. Common adverse events included nasopharyngitis, 
abdominal pain, and diarrhea. Serious adverse events occurred in 6 patients who 
received givosiran in parts A through C combined. In part C, all 6 patients who 
were assigned to receive once-monthly injections of givosiran had sustained 
reductions in ALAS1 messenger RNA (mRNA), delta aminolevulinic acid, and 
porphobilinogen levels to near normal. These reductions were associated with a 
79% lower mean annualized attack rate than that observed with placebo 
(exploratory efficacy end point).
CONCLUSIONS: Once-monthly injections of givosiran in patients who had recurrent 
porphyria attacks resulted in mainly low-grade adverse events, reductions in 
induced ALAS1 mRNA levels, nearly normalized levels of the neurotoxic 
intermediates delta aminolevulinic acid and porphobilinogen, and a lower attack 
rate than that observed with placebo. (Funded by Alnylam Pharmaceuticals; 
ClinicalTrials.gov number, NCT02452372 .).