title: Scientific and Regulatory Policy Committee Points-to-consider Paper*: Drug-induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part 2. Antisense Oligonucleotides.
abstract: Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. In recent years, DIVI has been occasionally observed in nonhuman primates given RNA-targeting therapeutics such as antisense oligonucleotide therapies (ASOs) during chronic toxicity studies. While DIVI in laboratory animal species has been well characterized for vasoactive small molecules, and immune-mediated responses against large molecule biotherapeutics have been well described, there is little published information regarding DIVI induced by ASOs to date. Preclinical DIVI findings in monkeys have caused considerable delays in development of promising new ASO therapies, because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans, and the lack of robust biomarkers of DIVI. This review of DIVI discusses clinical and microscopic features of vasculitis in monkeys, their pathogenic mechanisms, and points to consider for the toxicologist and pathologist when confronted with ASO-related DIVI. Relevant examples of regulatory feedback are included to provide insight into risk assessment of ASO therapies.
authors.affiliation: ISIS pharmaceuticals, Carlsbad, California, USA.
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Engelhardt
authors.affiliation: WIL Research Europe, Saint-Germain-Nuelles, France.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Fant
authors.affiliation: MedImmune, Cambridge, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Guionaud
authors.affiliation: ISIS pharmaceuticals, Carlsbad, California, USA.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Henry
authors.affiliation: Pfizer-Drug Safety Research and Development, Andover, Massachusetts, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Leach
authors.affiliation: Raritan, New Jersey, USA.
authors.forename: Calvert
authors.initials: C
authors.lastname: Louden
authors.affiliation: GlaxoSmithKline-Safety Assessment, King of Prussia, Pennsylvania, USA.
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Scicchitano
authors.affiliation: FDA, CDER, Silver Spring, Maryland, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Weaver
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: Tanja S
authors.initials: TS
authors.lastname: Zabka
authors.forename: Kendall S
authors.initials: KS
authors.lastname: Frazier
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000009:adverse effects*; D057772:Vascular System Injuries / Q000139:chemically induced*
chemical_list: D016376:Oligonucleotides, Antisense
keywords: antisense oligonucleotide; biomarkers; cardiovascular system; nonhuman primate; preclinical safety-assessment/risk management; vascular injury