Monoclonal Antibody Shows Promise in Mixed Dyslipidemia

Liam Davenport

June 02, 2022

MILAN — A single dose of a monoclonal antibody against an inhibitor of an enzyme involved in triglyceride degradation appears to substantially lower triglyceride and cholesterol levels, suggests a phase 1, first-in-human trial.

LY3475766 is a monoclonal antibody against the angiopoietin-like protein (ANGPTL)3/8 complex, a potent inhibitor of lipoprotein lipase, and was tested in 48 individuals with mixed dyslipidemia in an ascending-dose study.

It reduced triglyceride levels by up to 70%, alongside reductions in low-density-lipoprotein (LDL) cholesterol by up to 37%, apolipoprotein B by up to 31%, and increased high-density-lipoprotein (HDL) cholesterol by up to 26%.

With the antibody showing good tolerability and a favorable safety profile, Daniel Gaudet, MD, PhD, Department of Medicine, Université de Montréal, said that targeting ANGPTL3/8 shows promise.

"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 said. However, he acknowledged that further study is needed.

The research was presented at the European Atherosclerosis Society (EAS) 2022 Congress on May 23.

Commenting on the findings was S. Lale Tokgözoğlu, MD, PhD, professor of cardiology at Hacettepe University, Ankara, Turkey, who is chair of the EAS Scientific Program Committee.

She told theheart.org | Medscape Cardiology that it was important to study people with mixed dyslipidemia, as they are "likely to benefit from this agent, since it targets both LDL and triglycerides, and covers the atherogenic lipoproteins while increasing HDL cholesterol."

Moreover, "with the global epidemic of obesity and diabetes, mixed dyslipidemia with elevations in both triglycerides and LDL cholesterol are commonly seen."

Tokgözoğlu added that the potency of the molecule and its "unique aspect of lowering triglycerides and LDL without decreasing HDL" would make it suitable for decreasing both "cardiovascular risk in patients with mixed dyslipidemia and atherogenic dyslipidemia in diabetes and getting these patients to the secondary non-HDL cholesterol goals."

However, she urged caution in interpreting the results, saying that the dose of the monoclonal antibody will need to be "fine-tuned" to inhibit ANGPTL3 in order to avoid lipotoxicity while still achieving a clinical benefit.

"Attractive Combination, in Theory"

Gaudet noted that loss-of-function mutations in and pharmacologic inhibition of ANGPTL3 are associated with reduced levels of triglycerides and LDL cholesterol and increased levels of HDL cholesterol.

Moreover, individuals who are heterozygous for ANGPTL3 loss-of-function variants have a 41% reduced risk for coronary artery disease, compared with noncarriers.

Gaudet explained that ANGPTL8 is secreted in response to feeding, and variants truncating the protein are also associated with reduced triglyceride and LDL cholesterol levels, increased HDL cholesterol, and a reduced risk for coronary artery disease.

ANGPTL8 forms a complex with ANGPTL3 that inhibits lipoprotein lipase 100-fold more potently than ANGPTL3 alone, and circulates at much lower levels, he said, "making it a very attractive combination, in theory."

The researchers therefore conducted a phase 1, proof-of-concept randomized trial that involved 48 individuals with mixed hyperlipidemia, defined as a triglyceride level of at least 135 mg/dL and an LDL cholesterol level of at least 70 mg/dL.

They were assigned in a 6:2 ratio to one intravenous dose of LY3475766 10 mg to 30 mg, to one subcutaneous dose of LY3475766 100 mg to 600 mg, or to placebo.

The median age of the participants ranged from 44 to 56 years, and between 50% and 100% were male.

Gaudet showed that, after administration of the 600 mg subcutaneous dose of LY3475766, the half-life was 4.4 days, and that increases in the concentration of the ANGPTL3/8 complex matched exposure to LY3475766.

With the 100 mg, 300 mg, and 600 mg doses of LY3475766, the maximum decreases in triglycerides over baseline were approximately 59%, 65%, and 70%, respectively.

For LDL cholesterol, the maximum decreases in concentrations from baseline with the three doses were approximately 17%, 22%, and 37%, respectively, whereas for apolipoprotein B, decreases were 14%, 21%, and 31%, respectively.

Gaudet noted that there were also dose-related decreases in concentrations of remnant cholesterol from baseline to a maximum of 61% and in non-HDL cholesterol by up to 36%.

The largest increases in HDL cholesterol were seen with the 30 mg, 300 mg, and 600 mg doses, to a maximum of 26%.

In terms of safety, there were no serious adverse events and no treatment-emergent adverse events that prevented dose escalation, he said.

There was one case of intermittent asymptomatic second-degree atrioventricular block and another of asymptomatic monomorphic ventricular tachycardia.

There were two cases of mild injection-site edema and three cases of moderate site-injection pain, which all occurred "on the same day at the same site," Gaudet noted.

The study was sponsored by Eli Lilly and Company. Gaudet declares relationships with Aegerion, Allergan, Amgen, Novartis, Regeneron, Alcoa, Arrowhead, Eli Lilly, Ionis, Novo Nordisk, Pfizer, Sanofi, Acasti, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Ceapro, Dalcor, Esperion, Kowa, The Medicine Company, Uniqure, CRISPR Therapeutics, Saliogen, Verve Therapeutics.

European Atherosclerosis Society (EAS) 2022. Presented May 23, 2022.

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