Two phase 1 studies indicate that the monoclonal antibody evinacumab is well tolerated and lowers triglyceride levels in patients with hypertriglyceridemia by ≤80% within a few days of initiating treatment, according to study results published in Circulation.
The angiopoietin-like protein 3 (ANGPTL3) increases triglycerides and other lipids by inhibiting lipoprotein lipase activity. Evinacumab, a fully human monoclonal antibody, is an ANGPTL3 inhibitor that may lower cardiovascular risk by improving lipoprotein clearance.
Researchers assessed the safety and efficacy of evinacumab in participants with triglycerides >150 mg/dL but ≤450 mg/dL and low-density lipoprotein cholesterol ≥100 mg/dL in a single ascending-dose placebo-controlled study (SAD) (n=83) and a multiple ascending-dose placebo-controlled study (MAD) (n=56). Participants were randomly assigned 3:1 to an evinacumab group or placebo group. SAD study participants received subcutaneous (SC) evinacumab at 75/150/250 mg, or intravenous (IV) evinacumab at 5/10/20 mg/kg, monitored up to day 126. MAD study participants received SC evinacumab at 150/300/450 mg once a week, 300/450 mg every 2 weeks, or IV evinacumab at 20 mg/kg once every 4 weeks up to day 56, with 6 months of follow-up.
In the SAD study, 51.6% (n=32) of evinacumab participants reported treatment-emergent adverse events (TEAEs) compared with 42.9% (n=9) of placebo participants. In the MAD study, 67.7% (n=21) of SC evinacumab participants reported TEAEs compared with 75% (n=9) of SC placebo participants; 85.7% (n=6) of IV evinacumab participants reported TEAEs compared with 50% (n=1) of IV placebo participants.
The reported TEAEs were not serious, and no events led to death or discontinuation of treatment. Single, not-dose-related elevations in creatinine phosphokinase (2 [3.2%] SAD, 1 [14.3%] MAD), aspartate aminotransferase (4 [6.5%] SAD), and alanine aminotransferase (7 [11.3%] SAD) were observed with evinacumab compared with none in the placebo groups.
Both studies showed dose-dependent triglyceride reductions, with a maximum reduction of 83.1% at day 2 with 20 mg/kg IV once every 4 weeks (P =.0003) in the MAD study and 76.9% at day 3 with 10 mg/kg IV (P <.0001) in the SAD study.
Evinacumab also lowered low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, which likely contributed to the reductions in total cholesterol seen in both studies, but it did not significantly alter lipoprotein(a) levels.
Limitations of this study include small sample sizes, an absence of study subjects with extreme hypercholesterolemia, and problems with patient retention.
Study investigators concluded that ANGPTL3 inhibition with evinacumab therapy “was well-tolerated and lowered triglycerides by up to 80% within a few days in patients with elevated triglycerides. Treatment with evinacumab could be a strategy for those with severely elevated triglycerides.”
Several authors report connections with the pharmaceutical industry. Please see the reference for a full list of disclosures. Both studies were funded by Regeneron Pharmaceuticals, Inc.
Ahmad Z, Banerjee P, Hamon S, et al. Inhibition of angiopoietin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia [published online June 27, 2019]. Circulation. doi:10.1161/CIRCULATIONAHA.118.039107