Background and Aims

Angiopoietin-like protein 3 (ANGPTL3) inhibition reduces LDL-cholesterol (LDL-C), triglycerides (TG) and HDL-C in patients with hyperlipidemia. Post-prandially, ANGPTL8 forms a complex with ANGPTL3; the ANGPTL3/8 complex inhibits lipoprotein lipase 100-fold more potently and circulates at much lower levels than ANGPTL3 alone. This phase 1 study assessed the safety and pharmacology of single ascending doses of LY3475766 (LY), a monoclonal antibody against the ANGPTL3/8 complex.

Methods

This 28-day, randomized, double-blind, placebo-controlled study enrolled 48 subjects (36 males/12 females) with TG >135 mg/dL and LDL-C ≥70 mg/dL who were assigned (6:2) to receive 1 dose of LY or placebo intravenously (10 - 30mg) or subcutaneously (100 - 600mg). LY pharmacokinetics, fasting lipids, apolipoproteins, vital signs, laboratory data, and adverse events (AEs) were measured.

Results

LY reached maximum concentration 27-108 hours after subcutaneous injection; half-life for 600mg LY was 106 hours. Two weeks after LY subcutaneous injection, TG, remnant-cholesterol, LDL-C, non-HDL-C, and apolipoprotein B decreased dose-dependently. HDL-C increased with the two highest doses. Most common AEs were mild or moderate injection-site reactions, with no serious AEs or discontinuations due to AEs during the study.

Median percent change from baseline in fasting triglycerides (a) and remnant-cholesterol (b) and mean percent change from baseline in fasting LDL-C (c) and non-HDL-C (d) up to 28 days after single doses of LY3475766 or placebo. Intravenous doses (10mg and 30mg) not shown. (Remnant cholesterol=[total cholesterol]–[LDL-C]–[HDL-C]; LDL-C=LDL-cholesterol; HDL-C=HDL-cholesterol; LDL-C=LDL-cholesterol; SC=subcutaneous).

Conclusions

Inhibition of ANGPTL3/8 complex with LY reduced TG, remnant-cholesterol, LDL-C, non-HDL-C, and apolipoprotein B and increased HDL-C in patients with hyperlipidemia.