Abstract 19133: Inhibition of ANGPTL3 by Evinacumab Reduced Triglycerides (TGs) and LDL-C in Subjects Presenting With Modest Elevations in TGs and/or LDL-C, Recapitulating the Hypolipidemic Effects of Loss-of-Function (LoF) Mutations of ANGPTL3
Introduction: Elevations in LDL-C and TGs have been linked to increased CHD risk. Angiopoietin-like 3 (ANGPTL3) has a central role in lipid metabolism, and LoF mutations of ANGPTL3 in humans have been associated with reductions in TGs, LDL-C and HDL-C. Evinacumab (REGN1500) is a human monoclonal antibody specific for ANGPTL3 being developed for treatment of hyperlipidemia, including hypertriglyceridemia and hypercholesterolemia.
Methods: This phase 1, first-in-human, ascending single-dose, placebo (PBO)-controlled, double-blind study evaluated the safety and efficacy of evinacumab administered subcutaneously (SC) or intravenously (IV) in subjects with elevated TGs (150≤ TG ≤450 mg/dL) and/or LDL-C (≥100 mg/dL). The first part of the study randomized subjects to PBO (9, PBO SC; 12, PBO IV) and evinacumab (11, 75 mg SC; 12, 150 mg SC; 9, 250 mg SC; 10, 5 mg/kg IV; 9, 10 mg/kg IV; 11, 20 mg/kg IV).
Results: Evinacumab was well tolerated in this trial. Forty-one subjects reported at least one treatment emergent adverse event (TEAE): 32 [±51.6%] on evinacumab vs. 9 [±42.9%] on PBO. None were serious and no subject discontinued due to a TEAE. The most frequent TEAEs were headache (7 [11.3%] vs. 0 [0%]) and increase in ALT/AST (2 treated subjects were >3X ULN vs 0 on PBO, and 0 subjects were >5X ULN). There was no dose-related safety trend. Evinacumab effected dose-responsive reductions in TG (maximum reduction on Day 4) with median % changes from baseline of -1.0% to -75.0% from low to high dose vs +9.0% for PBO IV [p<0.0001]) and LDL-C (mean % changes of LDL-C from baseline on Day 11 were -3.4% to -25.5% from low to high dose vs -0.4% for PBO IV [p=0.0013]). The durations of 20 mg/kg TG and LDL reduction were also dose-dependent and extended to 64 and 43 days, respectively. Dose-dependent reductions in HDL-C, VLDL-C, total cholesterol, non-HDL-C, ApoA1, and ApoB were also observed but there were no apparent effects on Lp(a).
Conclusion: Administration of evinacumab in healthy subjects with moderately elevated TGs and/or LDL-C was generally well-tolerated. Evinacumab induced rapid and substantial reductions in TGs as well as reductions in LDL-C and HDL-C, recapitulating the observed hypolipoproteinemia in individuals homozygous for ANGPTL3 LoF mutations.
Author Disclosures: R. Dunbar: Research Grant; Modest; Merck. Honoraria; Modest; Regeneron. A. Bouzelmat: Employment; Significant; Regeneron Pharmaceuticals, Inc. D.A. Gipe: Employment; Significant; Regeneron Pharmaceuticals, Inc. R. Pordy: Employment; Significant; Regeneron Pharmaceuticals, Inc. W. Sasiela: Employment; Significant; Regeneron Pharmaceuticals, Inc. S. Mellis: Employment; Significant; Regeneron Pharmaceuticals, Inc. P. Banerjee: Employment; Significant; Regeneron Pharmaceuticals, Inc..
- © 2016 by American Heart Association, Inc.