Single doses of LY3475766, a monoclonal antibody to the ANGPTL3/8 complex, substantially reduced plasma TG and remnant cholesterol levels in patients with mixed dyslipidaemia. Data from the first in-human study in 48 patients with plasma TG levels >1.5 mmol/L (>135 mg/dL) and plasma LDL-C >1.8 mmol/L (70 mg/dL) showed maximum TG reductions of 59%, 65% and 70% at 15 days with LY3475766 100 mg, 300 mg and 600 mg respectively. LDL-C levels were reduced by a maximum of 17%, 22% and 37% respectively. Maximum decreases in apoB were 14%, 21% and 31%. There was also a dose dependent reduction in cholesterol remnants and a dose dependent increase in HDL-C.
“This HDL cholesterol result illustrates that the ANGPTL8 effect was greater than the ANGPTL3 effect because you would expect an ANGPTL3 inhibitor alone to lower HDL cholesterol,” commented Professor Daniel Gaudet, Université de Montréal & ECOGENE-21 Clinical & Translational Research Center, Chicoutimi, Québec, Canada, who presented the findings.
No serious adverse events or treatment emergent adverse events preventing dose escalation were reported. There was one case of intermittent asymptomatic 2nd degree atrioventricular block (Mobitz type 1) that was considered a likely normal variant by the investigator and one case of asymptomatic monomorphic ventricular tachycardia that was considered unrelated by the sponsor. There were also three cases of moderate injection site pain (two with LY3475766, one with placebo) all at the same centre on the same day; no abnormalities in laboratory safety data were detected.
Professor Gaudet explained that the ANGPTL3/8 complex is an interesting target because it is a 100 times more potent inhibitor of lipoprotein lipase (LpL), a key regulator of TG metabolism, than ANGPTL3 alone. The complex also circulates at much lower levels than ANGPTL3.
“Based on its effect on atherogenic apoB-containing lipoproteins, inhibition of the ANGPTL3/8 complex with LY3475766 may have the potential to reduce cardiovascular risk in patients with or at high risk for atherosclerotic cardiovascular disease on top of optimal standard of care,” he concluded.
Reference
Gaudet D, Gonciarz M, Shen X, et al. A first in-human single ascending dose study of a monoclonal antibody against the ANGPTL3/8 complex in subjects with mixed hyperlipidaemia. Presented at the 90th European Atherosclerosis Society Congress, Milan, Italy, May 22-25 2022, Late Breaker Session 1.
Reportage by Jenny Bryan