BACKGROUND: Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) 
therapeutic agent that inhibits the synthesis of proprotein convertase 
subtilisin-kexin type 9 (PCSK9), a target for the lowering of low-density 
lipoprotein (LDL) cholesterol.
METHODS: In this phase 1 trial, we randomly assigned healthy volunteers with an 
LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive 
a subcutaneous injection of inclisiran or placebo in either a 
single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a 
multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for 
two doses, or 300 or 500 mg monthly for two doses, with or without concurrent 
statin therapy); each dose cohort included four to eight participants. Safety, 
the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL 
cholesterol level, and exploratory lipid variables) were evaluated.
RESULTS: The most common adverse events were cough, musculoskeletal pain, 
nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were 
mild or moderate in severity. There were no serious adverse events or 
discontinuations due to adverse events. There was one grade 3 elevation in the 
γ-glutamyltransferase level, which was considered by the investigator to be 
related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg 
or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% 
from baseline to day 84), and doses of 100 mg or more reduced the LDL 
cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). 
Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 
for doses of 300 mg or more. All multiple-dose regimens reduced the levels of 
PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) 
and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline 
to day 84).
CONCLUSIONS: In this phase 1 trial, no serious adverse events were observed with 
inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly 
reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by 
Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, 
NCT02314442 .).