Physicians' Academy for Cardiovascular Education

First results with a monoclonal antibody against ANGPTL3/8 complex

News - May 24, 2022

A First-in-Human Single Ascending Dose Study of a Monoclonal Antibody against the ANGPLT3/8 Complex in Subjects with Mixed Hyperlipidemia

Presented at EAS 2022 by Daniel Gaudet (Montreal, QC, Canada)

Introduction and methods

Angiopoietin-like protein 3 (ANGPLT3) loss-of-function (LOF) mutations have been identified in families with low risk of CVD. Heterozygous carriers of ANGPLT3 LOF variants have a 41% lower risk of CAD than noncarriers. Pharmacological inhibition of ANGPTL3 is association with reduced levels of triglycerides, LDL-c and HDL-c.

ANGPTL8 is a cofactor of ANGPLT3 efficacy. In response to feeding, ANGPLT8 is secreted and forms a complex with ANGPLT3. ANGPLT8 protein-truncating variants are associated with lower triglyceride and LDL-c levels, and in contrast to ANGPLT3, with increased HDL-c levels, altogether resulting in decreased risk of CAD. The ANGPTL3/8 complex inhibits lipoprotein lipase (LPL) 100-fold more potently and circulates at much lower levels than ANGPTL3 alone, making it an interesting potential target.

In a phase I, single ascending dose study, a monoclonal antibody against the ANGPLT3/8 complex (LY345766) was examined. This was a randomized, double-blind, placebo-controlled study over 28 days in 48 subjects with mixed hyperlipidemia (TG ≥135 mg/dL [≥1.5 mmol/L] and LDL-c ≥70 mg/dL [≥1.8 mmol/L). There were 5 cohorts of LY3475766: 10 mg (n=6) and 30 mg (n=6) IV, and 100 mg (n=6), 300 mg (n=12) and 600 mg (n=6) SC; and placebo-treated subjects (pooled; n=12).

The primary objective was safety and tolerability. Secondary objectives were pharmacokinetics of LY347566, changes in fasting serum ANGPLT3/8 from baseline and changes in fasting serum lipids and lipoproteins from baseline.

Main results


A single dose administration of the monoclonal antibody against LY3475766 resulted in dose-dependent increase in fasting ANGPLT3/8 levels. Lipid changes were as follows: up to 70% of TG, up to 61% of remnant cholesterol, up to 37% for LDL-c, up to 36% for non-HDL-c, up to 31% for apoB and an increase up to 26% of HDL-c. Moreover, LY3475655 had a good safety and tolerability profile.

– Our coverage of EAS 2022 is based on the information provided during the congress –

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