title: Integrated Safety Assessment of 2'-O-Methoxyethyl Chimeric Antisense Oligonucleotides in NonHuman Primates and Healthy Human Volunteers.
abstract: The common chemical and biological properties of antisense oligonucleotides provide the opportunity to identify and characterize chemical class effects across species. The chemical class that has proven to be the most versatile and best characterized is the 2'-O-methoxyethyl chimeric antisense oligonucleotides. In this report we present an integrated safety assessment of data obtained from controlled dose-ranging studies in nonhuman primates (macaques) and healthy human volunteers for 12 unique 2'-O-methoxyethyl chimeric antisense oligonucleotides. Safety was assessed by the incidence of safety signals in standardized laboratory tests for kidney and liver function, hematology, and complement activation; as well as by the mean test results as a function of dose level over time. At high doses a number of toxicities were observed in nonhuman primates. However, no class safety effects were identified in healthy human volunteers from this integrated data analysis. Effects on complement in nonhuman primates were not observed in humans. Nonhuman primates predicted safe doses in humans, but over predicted risk of complement activation and effects on platelets. Although limited to a single chemical class, comparisons from this analysis are considered valid and accurate based on the carefully controlled setting for the specified study populations and within the total exposures studied.
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
authors.forename: Stanley T
authors.initials: ST
authors.lastname: Crooke
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Baker
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
authors.forename: T Jesse
authors.initials: TJ
authors.lastname: Kwoh
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Schulz
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
authors.forename: Shuting
authors.initials: S
authors.lastname: Xia
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
authors.forename: Nelson
authors.initials: N
authors.lastname: Salgado
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
authors.forename: Huynh-Hoa
authors.initials: HH
authors.lastname: Bui
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Hart
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
authors.forename: Sebastien A
authors.initials: SA
authors.lastname: Burel
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.|Current address: NGM Biopharmaceuticals, San Francisco, California, USA.
authors.forename: Husam S
authors.initials: HS
authors.lastname: Younis
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Geary
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Henry
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, California, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D064368:Healthy Volunteers; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D008738:Methyl Ethers / Q000737:chemistry*; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry*; D013873:Thionucleotides / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry*; D055815:Young Adult
chemical_list: D008738:Methyl Ethers; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides