Inhibiting ANGPTL4 in the liver, using a hepatocyte-targeting GalNAc-conjugated antisense oligonucleotide (ASO), may be a promising way of lowering TG and other lipids, without down regulating ANGPTL4 expression in lymphatic macrophages. In previous mouse studies with non-targeted ASOs, down regulation of ANGPTL4 expression in lymphatic macrophages was associated with lymphadenopathy.
In two late-breaker presentations, Dr Stefan Nilsson, Lipigon Pharmaceuticals, Umeå, Sweden, reported pre-clinical data supporting the safety of the new approach.1,2
In studies with C57Bl/6 mice fed a high fat diet, dose-dependent effects of targeted, murine-specific ANGPTL4 ASOs were seen in reductions in TG, VLDL, total cholesterol and LDL-C, compared to animals treated with negative control ASOs.1 Mice treated with ANGPTL4 ASOs also gained significantly less weight, showed reduced food intake, exhibited superior glucose tolerance, and had lower serum amyloid A levels. No significant difference in plasma alanine aminotransferase activity was observed, and treatment did not induce lymphadenopathy.
In a second presentation, Dr Nilsson reported pre-clinical data showing that the GalNAc-conjugated ASO, A24110He, under development for treatment of severe hypertriglyceridaemia and familial chylomicronaemia syndrome (FCS), was tolerable at doses up to 30 mg/kg in cynomolgus monkeys and up to 50 mg/kg in rats, after 28 days of dosing.2 In the cynomolgus monkeys, liver concentrations of A24110He per gram of tissue were approximately 15 times those seen in 1 ml of plasma.
A double blind, placebo controlled, first in human study to test the safety, tolerability, pharmacokinetics and pharmacodynamics of A24110He 100 mg s.c in healthy volunteers will start shortly, with last patient visits planned for May 2023.
References
- Nilsson SK. Silencing of ANGPTL4 via antisense oligonucleotides effectively reduces plasma triglyceride and glucose levels in mice without causing lymphadenopathy. Presented at the 90th European Atherosclerosis Society Congress, Milan, Italy, May 22-25 2022, Late Breaker Session 2.
- Nilsson SK. Liver specific targeting of ANGPTL4 using a GalNac conjugated antisense oligonucleotides approach. Presented at the 90th European Atherosclerosis Society Congress, Milan, Italy, May 22-25 2022, Late Breaker Session 2.
Reportage by Jenny Bryan