First results with a monoclonal antibody against ANGPTL3/8 complex

EAS 2022 The ANGPLT3/8 complex inhibits LPL 100-fold more potently than ANGPLT3 alone, making this complex an attractive target for CVD prevention 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

• There were no serious adverse events and no treatment-emergent adverse events preventing dose escalation. There were 2 cases of mild injection site edema in active-treated subjects and 3 cases of moderate injection site pain (2 active, 1 placebo).
• With SC administration, Tmax ranged from 1 to 4.5 days; and with 600 mg SC administration the half-life was 4.4 days.
• Increases in ANGPLT3/8 complex matched LY347566 drug exposure.
• Triglyceride levels decreased maximally by 59%, 65% and 70% with 100, 300 and 600 mg doses, respectively. Also, dose-related decreases in remnant cholesterol were observed.
• LDL-c decreased maximally by 17%, 22% and 37% with 100, 300 and 600 mg doses, respectively. Increase in HDL-c was greatest with 30, 300 and 600 mg doses.
• Dose-related decreases in non-HDL-c were observed with 100, 300 and 600 mg doses.
• ApoB was maximally decreased by 14%, 21% and 31% with 100, 300 and 600 mg doses, respectively.

Conclusion

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 –