Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys.
Level 5 - mechanism / opinion, no new human data
Preclinical animal model (rhesus monkeys) and in vitro laboratory assays.
PubMed 26934220 · doi:10.1038/nature17180
What was done
Researchers evaluated GS-5734 (a monophosphoramidate prodrug of an adenosine analogue) in cell-based assays against filoviruses and other RNA viruses, and assessed active nucleoside triphosphate (NTP) formation and chain termination. Pharmacokinetics and tissue distribution to sanctuary sites (testes, eyes, brain) were evaluated in nonhuman primates. In a rhesus monkey model of Ebola virus disease (EVD), monkeys were treated with once-daily intravenous GS-5734 at 10 mg/kg for 12 days initiated three days post-exposure, when systemic viral RNA was detectable in two of six treated animals.
What was found
GS-5734 active NTP exhibited a 14-hour half-life in peripheral blood mononuclear cells and distributed to sanctuary sites in nonhuman primates. In the rhesus monkey challenge model, 10 mg/kg daily GS-5734 resulted in 100% survival against lethal disease, suppressed viral replication, and improved clinical signs and pathophysiological markers. Broad-spectrum in vitro activity was also reported against other filoviruses, arenaviruses, and coronaviruses.
Why it matters
This study provides proof-of-concept for GS-5734 (later known as remdesivir) as a small-molecule antiviral capable of post-exposure protection against lethal Ebola virus infection in nonhuman primates with tissue penetration into viral sanctuary sites.
Limits
The study is limited to in vitro assays and a nonhuman primate model; human clinical efficacy and safety were not established. The total sample size and control group numbers are not detailed in the abstract, and treatment was initiated at a fixed early time point (day 3 post-exposure) with viral RNA detectable in only 2 of 6 treated animals at baseline.
Cited by
- supports Remdesivir was originally developed as a treatment for Ebola.