title: Safety and pharmacokinetic profiles of phosphorodiamidate morpholino oligomers with activity against ebola virus and marburg virus: results of two single-ascending-dose studies.
abstract: Two identical single-ascending-dose studies evaluated the safety and pharmacokinetics (PK) of AVI-6002 and AVI-6003, two experimental combinations of phosphorodiamidate morpholino oligomers with positive charges (PMOplus) that target viral mRNA encoding Ebola virus and Marburg virus proteins, respectively. Both AVI-6002 and AVI-6003 were found to suppress disease in virus-infected nonhuman primates in previous studies. AVI-6002 (a combination of AVI-7537 and AVI-7539) or AVI-6003 (a combination of AVI-7287 and AVI-7288) were administered as sequential intravenous (i.v.) infusions of a 1:1 fixed dose ratio of the two subcomponents. In each study, 30 healthy male and female subjects between 18 and 50 years of age were enrolled in six-dose escalation cohorts of five subjects each and received a single i.v. infusion of active study drug (0.005, 0.05, 0.5, 1.5, 3, and 4.5 mg/kg per component) or placebo in a 4:1 ratio. Both AVI-6002 and AVI-6003 were safe and well tolerated at the doses studied. A maximum tolerated dose was not observed in either study. The four chemically similar PMOplus components exhibited generally similar PK profiles. The mean peak plasma concentration and area under the concentration-time curve values of the four components exhibited dose-proportional PK. The estimated plasma half-life of all four components was 2 to 5 h. The safety of the two combinations and the PK of the four components were similar, regardless of the target RNA sequence.
authors.affiliation: Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA healda@uw.edu.
authors.forename: Alison E
authors.initials: AE
authors.lastname: Heald
authors.affiliation: Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA Oregon State University, Corvallis, Oregon, USA.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Iversen
authors.affiliation: Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA.
authors.forename: Jay B
authors.initials: JB
authors.lastname: Saoud
authors.affiliation: Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Sazani
authors.affiliation: Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Charleston
authors.affiliation: Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Axtelle
authors.affiliation: Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wong
authors.affiliation: New Orleans Center for Clinical Research-Knoxville, Knoxville, Tennessee, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Smith
authors.affiliation: West Coast Clinical Trials, Cypress, California, USA.
authors.forename: Apinya
authors.initials: A
authors.lastname: Vutikullird
authors.affiliation: Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Kaye
mesh_terms: D000328:Adult; D000818:Animals; D019540:Area Under Curve; D004311:Double-Blind Method; D029043:Ebolavirus / Q000187:drug effects / Q000235:genetics; D005260:Female; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008379:Marburg Virus Disease / Q000188:drug therapy* / Q000821:virology; D029024:Marburgvirus / Q000187:drug effects / Q000235:genetics; D008875:Middle Aged; D060172:Morpholinos / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010919:Placebos; D055815:Young Adult
chemical_list: D060172:Morpholinos; D010919:Placebos