title: Preclinical evaluation of the toxicological effects of a novel constrained ethyl modified antisense compound targeting signal transducer and activator of transcription 3 in mice and cynomolgus monkeys.
abstract: ISIS 481464 is a constrained ethyl (cEt) modified phosphorothioate antisense oligonucleotide (ASO) targeting signal transducer and activator of transcription 3 (STAT3) studied in mice and monkey to support oncology clinical trials. Six-week toxicology studies were performed in mice and cynomolgus monkey (up to 70 and 30 mg/kg/week respectively). Reduction in STAT3 protein up to 90% of control was observed in monkey. Cynomolgus monkey was considered the most relevant species to human with respect to pharmacokinetic properties, but mice are useful in their relative sensitivity to the potential proinflammatory and hepatic effects of oligonucleotides. In monkeys, there was no impact on organ function at doses up to 30 mg/kg/week for 6 weeks. Minimal to slight proximal tubular epithelial cell degeneration and regeneration within the kidney was observed, which had no impact on renal function and showed reversibility at the end of the treatment-free period. Additionally, mild and transient activated partial thromboplastin time elevations and mild increases in complement Bb were observed at the higher doses by intravenous dosing only. In mice, the alterations at 70 mg/kg/week included spleen weight increase up to 1.4-fold relative to control, increases in alanine aminotransferase and aspartate aminotransferase up to 1.8-fold over control, interleukin-10 increases up to 3.7-fold, and monocyte chemoattractant protein-1 increase up to 1.9-fold over control. No significant clinical pathology or histopathology changes were seen in mice at 20 mg/kg/week or less. The toxicity profile of ISIS 481464 is consistent with effects observed with phosphorothioate ASOs containing 2'-O-methoxyethylribose modifications instead of cEt.
authors.affiliation: Isis Pharmaceuticals, Carlsbad, California 92010, USA. sburel@isisph.com
authors.forename: Sebastien A
authors.initials: SA
authors.lastname: Burel
authors.forename: So-Ri
authors.initials: SR
authors.lastname: Han
authors.forename: Hong-Soo
authors.initials: HS
authors.lastname: Lee
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Norris
authors.forename: Byoung-Seok
authors.initials: BS
authors.lastname: Lee
authors.forename: Todd
authors.initials: T
authors.lastname: Machemer
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Park
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Zhou
authors.forename: Guobin
authors.initials: G
authors.lastname: He
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.forename: A Robert
authors.initials: AR
authors.lastname: MacLeod
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: Shirley
authors.initials: S
authors.lastname: Lio
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Kim
authors.forename: Scott P
authors.initials: SP
authors.lastname: Henry
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D010314:Partial Thromboplastin Time; D054735:Phosphorothioate Oligonucleotides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000633:toxicity*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D013154:Spleen / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D050796:STAT3 Transcription Factor; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase