Inhibition of Angiopoietin-Like Protein 3 With a Monoclonal Antibody Reduces Triglycerides in Hypertriglyceridemia

Zahid Ahmad, Poulabi Banerjee, Sara Hamon, Kuo-Chen Chan, Aurelie Bouzelmat, William J Sasiela, Robert Pordy, Scott Mellis, Hayes Dansky, Daniel A Gipe, Richard L Dunbar, Zahid Ahmad, Poulabi Banerjee, Sara Hamon, Kuo-Chen Chan, Aurelie Bouzelmat, William J Sasiela, Robert Pordy, Scott Mellis, Hayes Dansky, Daniel A Gipe, Richard L Dunbar

Abstract

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.

Keywords: cardiovascular disease; clinical trial; hypertriglyceridemia; lipids and lipoprotein metabolism.

Figures

Figure 1.
Figure 1.
Percent median (Q1–Q3) change from baseline. Percent median (Q1–Q3) change from baseline in (A) triglycerides, (B) absolute median triglyceride levels, and percent LSM (SE) change from baseline in (C) VLDL-C, (D) LDL-C, and (E) HDL-C in subjects with multiple dyslipidemia (single ascending dose study). EOS indicates end of study; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LSM, least-squares mean; and VLDL-C, very-low-density lipoprotein cholesterol.
Figure 2.
Figure 2.
Percent median (Q1–Q3) change from baseline. Percent median (Q1–Q3) change from baseline in (A) triglycerides, (B) absolute median triglyceride levels, and percent LSM (SE) change from baseline in (C) VLDL-C, (D) LDL-C, and (E) HDL-C in subjects with elevated triglycerides and LDL-C (multiple ascending dose study). HDL-C indicates high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LSM, least-squares mean; Q2W, every 2 weeks; Q4W, once every 4 weeks; QW, once per week; and VLDL-C, very low-density lipoprotein cholesterol.

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