Antivenom is currently the standard-of-care treatment for
snakebite envenoming, but its efficacy is limited by
treatment delays, availability, and in many cases, species specificity. Many of the rapidly lethal effects of envenoming are caused by
venom-derived toxins, such as
phospholipase A2 (
sPLA2); therefore, small molecule direct toxin inhibitors targeting these toxins may have utility as initial and adjunct
therapies after envenoming.
Varespladib (intravenous, IV) and
varespladib-methyl (oral) have been shown to potently inhibit
sPLA2s from
snake venoms in murine and porcine models, thus supporting their further study as potential treatments for
snakebite envenoming. In this pilot study, we tested the ability of these compounds to reverse neurotoxic effects of
venom from the Australian and Papuan taipan (Oxyuranus scutellatus) subspecies in juvenile pigs (Sus domesticus). The mean survival time for control animals receiving Australian taipan
venom (0.03 mg/kg, n = 3) was 331 min ± 15 min; for those receiving Papuan taipan
venom (0.15 mg/kg, n = 3) it was 178 ± 31 min. Thirteen pigs received Australian taipan
venom and treatment with either IV or oral
varespladib (or with IV to oral transition) and all 13 survived the duration of the study (≥96 h). Eight pigs received Papuan taipan
venom followed by treatment: Briefly: Two animals received
antivenom immediately and survived to the end of the study. Two animals received
antivenom treatment delayed 45 min from envenoming and died within 4 h. Two animals received similarly delayed
antivenom treatment and were rescued by
varespladib. Two animals were treated with
varespladib alone after a 45-min delay. Treatment with
varespladib only was effective but required repeat dosing over the course of the study. Findings highlight both the importance of early treatment and, as well, a half-life for the investigational inhibitors now in Phase II clinical trials for
snakebite.
Varespladib rapidly reversed weakness even when administered many hours post-envenoming and, overall, our results suggest that
varespladib and
varespladib-methyl could be efficacious tools in the treatment of sPLA2-induced weakness from Oxyuranus envenoming. Further clinical study as initial
therapy and as potential method of rescue from some types of
antivenom-resistant envenomings are supported by these data.