title: AVI-7288 for Marburg Virus in Nonhuman Primates and Humans.
abstract: BACKGROUND
  AVI-7288 is a phosphorodiamidate morpholino oligomer with positive charges that targets the viral messenger RNA that encodes Marburg virus (MARV) nucleoprotein. Its safety in humans is undetermined.
  
  
  METHODS
  We assessed the efficacy of AVI-7288 in a series of studies involving a lethal challenge with MARV in nonhuman primates. The safety of AVI-7288 was evaluated in a randomized, multiple-ascending-dose study in which 40 healthy humans (8 humans per dose group) received 14 once-daily infusions of AVI-7288 (1 mg, 4 mg, 8 mg, 12 mg, or 16 mg per kilogram of body weight) or placebo, in a 3:1 ratio. We estimated the protective dose in humans by comparing pharmacokinetic variables in infected nonhuman primates, uninfected nonhuman primates, and uninfected humans.
  
  
  RESULTS
  Survival in infected nonhuman primates was dose-dependent, with survival rates of 0%, 30%, 59%, 87%, 100%, and 100% among monkeys treated with 0 mg, 3.75 mg, 7.5 mg, 15 mg, 20 mg, and 30 mg of AVI-7288 per kilogram, respectively (P<0.001 with the use of the log-rank test for the comparison of survival across groups). No safety concern was identified at doses up to 16 mg per kilogram per day in humans. No serious adverse events were reported. Drug exposure (the area under the curve) was dose-dependent in both nonhuman primates and humans; drug clearance was independent of dose but was higher in nonhuman primates than in humans. The protective dose in humans was initially estimated, on the basis of exposure, to be 9.6 mg per kilogram per day (95% confidence interval, 6.6 to 12.5) for 14 days. Monte Carlo simulations supported a dose of 11 mg per kilogram per day to match the geometric mean protective exposure in nonhuman primates.
  
  
  CONCLUSIONS
  This study shows that, on the basis of efficacy in nonhuman primates and pharmacokinetic data in humans, AVI-7288 has potential as postexposure prophylaxis for MARV infection in humans. (Funded by the Department of Defense; ClinicalTrials.gov number, NCT01566877.).
authors.affiliation: From Sarepta Therapeutics, Cambridge, MA (A.E.H., J.S.C., P.L.I., J.B.S., P.S., M.W., D.B., E.M.K.); Division of Infectious Diseases, University of Washington, Seattle (A.E.H.); Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis (P.L.I.); and Therapeutic Discovery Center, Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick (T.K.W., J.W., K.L.W., D.L.S., L.S.W., S.B.), and SNBL Clinical Pharmacology Center, Baltimore (M.A.-I.) - both in Maryland.
authors.forename: Alison E
authors.initials: AE
authors.lastname: Heald
authors.forename: Jay S
authors.initials: JS
authors.lastname: Charleston
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Iversen
authors.forename: Travis K
authors.initials: TK
authors.lastname: Warren
authors.forename: Jay B
authors.initials: JB
authors.lastname: Saoud
authors.forename: Mohamed
authors.initials: M
authors.lastname: Al-Ibrahim
authors.forename: Jay
authors.initials: J
authors.lastname: Wells
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Warfield
authors.forename: Dana L
authors.initials: DL
authors.lastname: Swenson
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Welch
authors.forename: Peter
authors.initials: P
authors.lastname: Sazani
authors.forename: Michael
authors.initials: M
authors.lastname: Wong
authors.forename: Diane
authors.initials: D
authors.lastname: Berry
authors.forename: Edward M
authors.initials: EM
authors.lastname: Kaye
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053208:Kaplan-Meier Estimate; D008252:Macaca fascicularis; D008379:Marburg Virus Disease / Q000188:drug therapy* / Q000401:mortality; D029024:Marburgvirus / Q000235:genetics; D060172:Morpholinos / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012333:RNA, Messenger; D012367:RNA, Viral
chemical_list: C000599943:AVI-7288; D000998:Antiviral Agents; D060172:Morpholinos; D012333:RNA, Messenger; D012367:RNA, Viral