AVI-7288 for Marburg Virus in Nonhuman Primates and Humans.
Author(s): Heald AE(1), Charleston JS, Iversen PL, Warren TK, Saoud JB, Al-Ibrahim M, Wells
J, Warfield KL, Swenson DL, Welch LS, Sazani P, Wong M, Berry D, Kaye EM, Bavari
S.
Affiliation(s): Author information:
(1)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.
Publication date & source: 2015, N Engl J Med. , 373(4):339-48
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.).
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