BACKGROUND: Hypertriglyceridemia is associated with increased cardiovascular 
risk and may be caused by impaired lipoprotein clearance. Angiopoietin-like 
protein 3 (ANGPTL3) inhibits lipoprotein lipase activity, increasing 
triglycerides and other lipids. Evinacumab, an ANGPTL3 inhibitor, reduced 
triglycerides in healthy human volunteers and in homozygous familial 
hypercholesterolemic individuals. Results from 2 Phase 1 studies in 
hypertriglyceridemic subjects are reported here.
METHODS: Subjects with triglycerides >150 but ≤450 mg/dL and low-density 
lipoprotein cholesterol ≥100 mg/dL (n=83 for single ascending dose study [SAD]; 
n=56 for multiple ascending dose study [MAD]) were randomized 3:1 to 
evinacumab:placebo. SAD subjects received evinacumab subcutaneously at 
75/150/250 mg, or intravenously at 5/10/20 mg/kg, monitored up to day 126. MAD 
subjects received evinacumab subcutaneously at 150/300/450 mg once weekly, 
300/450 mg every 2 weeks, or intravenously at 20 mg/kg once every 4 weeks up to 
day 56 with 6 months of follow-up. The primary outcomes were incidence and 
severity of treatment-emergent adverse events. Efficacy analyses included 
changes in triglycerides and other lipids over time.
RESULTS: In the SAD, 32 (51.6%) versus 9 (42.9%) subjects on evinacumab versus 
placebo reported treatment-emergent adverse events. In the MAD, 21 (67.7%) 
versus 9 (75.0%) subjects on subcutaneously evinacumab versus placebo and 6 
(85.7%) versus 1 (50.0%) on intravenously evinacumab versus placebo reported 
treatment-emergent adverse events. No serious treatment-emergent adverse events 
or events leading to death or treatment discontinuation were reported. 
Elevations in alanine aminotransferase (7 [11.3%] SAD), aspartate 
aminotransferase (4 [6.5%] SAD), and creatinine phosphokinase (2 [3.2%) SAD, 1 
[14.3%] MAD) were observed with evinacumab (none in the placebo groups), which 
were single elevations and were not dose-related. Dose-dependent reductions in 
triglycerides were observed in both studies, with maximum reduction of 76.9% at 
day 3 with 10 mg/kg intravenously (P<0.0001) in the SAD and of 83.1% at day 2 
with 20 mg/kg intravenously once every 4 weeks (P=0.0003) in the MAD. 
Significant reductions in other lipids were observed with most evinacumab doses 
versus placebo.
CONCLUSION: Evinacumab was well-tolerated in 2 Phase 1 studies. Lipid changes in 
hypertriglyceridemic subjects were similar to those observed with ANGPTL3 
loss-of-function mutations. Because the latter is associated with reduced 
cardiovascular risk, ANGPTL3 inhibition may improve clinical outcomes.
CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifiers: 
NCT01749878 and NCT02107872.