Liver specific targeting of ANGPTL4 using a galnac conjugated antisense oligonucleotides approach

Background and Aims : Elevated plasma triglyceride is a marker of increased risk for cardiovascular disease and has been of interest for intensive drug development the last decade. Targets regulating the lipoprotein lipase system, such as ANGPTL3 and APOC3, have been in focus using different modalities, e.g. mAB and RNA based drugs. Recent genetetic studies using mendelian randomization, by us (unpublished) and others (published), suggests that ANGPTL4 is a far better target for both CAD and T2D than established targets ANGPTL3 and APOC3. Moreover, ANGPTL4 has also been linked to kidney function and liver fat content. We have shown, using a murine ANGPTL4-ASO tool compouind, that ANGPTL4 could be a safe target (submitted data). Here we aim showing the nonclinical safety profile of the human drug candidate A24110He.Methods: A24110He is a drug candidate being developed for the treatment of Severe Hypertriglyceremia (SHTG) and Familiar Chylomicronaemia Syndrome (FCS). A24110He is an antisense oligonucleotide targeting the mRNA of Angiopoietin-like 4 (ANGPTL4) protein, which modulates triacylglycerol homeostasis through its inhibitory effect on lipoprotein lipase (LPL) activity. A24110He was tested in vitro and in vivo for safety parameters and efficacy.Results: A24110He was found to efficiently decrease ANGPTL4 mRNA in various human and animal cells. In vivo it was was well tolerated in mice, rats and cynomolgus monkey. Significant reduction on plasma triacylglycerol was seen both in rats and cynomolgus monkey.Conclusions: In conclusion, the safety pharmacology studies indicate that A24110He will not cause any adverse effects at the doses intended to be used in a planned clinical trial. Background and Aims : Elevated plasma triglyceride is a marker of increased risk for cardiovascular disease and has been of interest for intensive drug development the last decade. Targets regulating the lipoprotein lipase system, such as ANGPTL3 and APOC3, have been in focus using different modalities, e.g. mAB and RNA based drugs. Recent genetetic studies using mendelian randomization, by us (unpublished) and others (published), suggests that ANGPTL4 is a far better target for both CAD and T2D than established targets ANGPTL3 and APOC3. Moreover, ANGPTL4 has also been linked to kidney function and liver fat content. We have shown, using a murine ANGPTL4-ASO tool compouind, that ANGPTL4 could be a safe target (submitted data). Here we aim showing the nonclinical safety profile of the human drug candidate A24110He. Methods: A24110He is a drug candidate being developed for the treatment of Severe Hypertriglyceremia (SHTG) and Familiar Chylomicronaemia Syndrome (FCS). A24110He is an antisense oligonucleotide targeting the mRNA of Angiopoietin-like 4 (ANGPTL4) protein, which modulates triacylglycerol homeostasis through its inhibitory effect on lipoprotein lipase (LPL) activity. A24110He was tested in vitro and in vivo for safety parameters and efficacy. Results: A24110He was found to efficiently decrease ANGPTL4 mRNA in various human and animal cells. In vivo it was was well tolerated in mice, rats and cynomolgus monkey. Significant reduction on plasma triacylglycerol was seen both in rats and cynomolgus monkey. Conclusions: In conclusion, the safety pharmacology studies indicate that A24110He will not cause any adverse effects at the doses intended to be used in a planned clinical trial.