<p>Loss-of-function variants in the gene encoding angiopoietin-like protein 3 (ANGPTL3) are associated with decreased triglyceride and low-density lipoprotein cholesterol levels, as well as with lower cardiovascular risk. Here we describe a 16-week phase 1 trial of zodasiran, an <i>ANGPTL3</i>‑targeting small interfering RNA, in patients on lipid-lowering therapy with either hyperlipidemia (with a placebo control arm) (<i>n</i> = 9; 7 male and 2 female), familial hypercholesterolemia (<i>n</i> = 17; 9 male and 8 female) or moderate-to-severe hypertriglyceridemia (<i>n</i> = 6; 4 male and 2 female). Patients received zodasiran subcutaneously on days 1 and 29, followed by a 48-week open-label extension in the familial hypercholesterolemia cohort (<i>n</i> = 13; 7 male and 6 female) in which zodasiran was dosed every 12 weeks. No serious treatment-related adverse events, the primary endpoint of the trial, were observed. Moreover, no elevations in hepatic aminotransferases, bilirubin or glycated hemoglobin were observed, and there were no drug discontinuations. All cohorts showed reductions at week 16 (12 weeks postdosing) in serum ANGPTL3 (≤−85.4%) and triglycerides (≤−67.1%), which were secondary endpoints. Reduction in ANGPTL3 was sustained to end-of-open-label extension in the familial hypercholesterolemia cohort. These results indicate a favorable safety profile for zodasiran, with promise for correcting isolated hypercholesterolemia and moderate-to-severe hypertriglyceridemia, and support further studies of zodasiran in treating a wide spectrum of dyslipidemias. ClinicalTrials.gov registration: <a href="https://clinicaltrials.gov/study/NCT03747224">NCT03747224</a>.</p>