title: Repeat-dose toxicology evaluation in cynomolgus monkeys of AVI-4658, a phosphorodiamidate morpholino oligomer (PMO) drug for the treatment of duchenne muscular dystrophy.
abstract: AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) drug designed to restore dystrophin expression in a subset of patients with Duchenne muscular dystrophy (DMD). Previous reports demonstrated this clinical proof-of-principle in patients with DMD following intramuscular injection of AVI-4658. This preclinical study evaluated the toxicity and toxicokinetic profile of AVI-4658 when administered either intravenously (IV) or subcutaneously (SC) to cynomolgus monkeys once weekly over 12 weeks, at doses up to the maximum feasible dose of 320 mg/kg per injection. No drug-related effects were noted on survival, clinical observations, body weight, food consumption, opthalmoscopic or electrocardiographic evaluations, hematology, clinical chemistry, urinalysis, organ weights, and macroscopic evaluations. Drug-related microscopic renal effects were dose-dependent, apparently reversible, and included basophilic granules (minimal), basophilic tubules (minimal to moderate), and tubular vacuolation (minimal to mild). These data establish the tolerability of AVI-4658 at doses up to and including the maximum feasible dose of 320 mg/kg by IV bolus or SC injection.
authors.affiliation: AVI BioPharma, Bothell, WA 98021, USA. psazani@avibio.com
authors.forename: Peter
authors.initials: P
authors.lastname: Sazani
authors.forename: Kirk P Van
authors.initials: KP
authors.lastname: Ness
authors.forename: Doreen L
authors.initials: DL
authors.lastname: Weller
authors.forename: Duane W
authors.initials: DW
authors.lastname: Poage
authors.forename: Kiran
authors.initials: K
authors.lastname: Palyada
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Shrewsbury
mesh_terms: D000818:Animals; D001483:Base Sequence; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D060172:Morpholinos; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy*; D009841:Oligonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*
chemical_list: D060172:Morpholinos; D009841:Oligonucleotides; C000611335:eteplirsen