Intravenous Followed by Oral Varespladib as Late Adjunctive Therapy for Snakebite: a Phase II Randomized Clinical Trial

Snakebite envenoming causes an estimated 138,000 deaths and more than 400,000 cases of permanent disability each year, disproportionately affecting low-resource regions. Antivenom is the only treatment but requires intravenous administration. We evaluated intravenous followed by oral varespladib as adjunctive therapy to antivenom in hospitalized patients with snakebite envenoming.

Methods and findings

In this multicenter, randomized, double-blind, placebo-controlled phase II trial in India (CTRI/2023/10/058782) and the USA ( NCT05717062 ), patients with snakebite envenoming were randomly assigned (1:1) to receive varespladib or placebo in addition to standard of care. For elapid envenoming, the primary endpoint was time to recovery of 5-second head-lift. For viper envenoming, the primary endpoint was area under the curve (AUC) from baseline to Day 14 of a 3-item Snakebite Severity Score (SSS). Between June 3 ^rd , 2023 and October 19 ^th , 2024, 140 patients were randomized and 139 were analyzed (73 varespladib; 66 placebo). Study drug was initiated a mean of 7.3 hours after the bite and 3.3 hours after antivenom. Among elapid-bite patients, mean time to head-lift recovery was 27.6 hours with varespladib vs. 36.2 hours with placebo (p = 0.6). Among viper-bite patients, SSS AUC to Day 14 was 660 vs. 629 in varespladib vs. placebo (p = 0.7). No serious adverse event occurred with varespladib.

Conclusions

In this trial in which varespladib was initiated on average 7 hours after snakebite and several hours after antivenom, adjunctive varespladib did not improve the primary endpoints. Other study designs and settings will be needed to assess the effect of varespladib when initiated prior to antivenom.

Synopsis

Snakebite envenoming causes more than 100,000 deaths and hundreds of thousands of cases of long-term disability each year, primarily in low- and middle-income countries. Antivenom is the only specific treatment currently available, but it must be administered intravenously in a healthcare facility and may not fully neutralize venom toxins that have already entered tissues. Varespladib is a small-molecule drug that inhibits secretory phospholipase A2, a toxin family found in many medically important snakes. Animal studies suggest that varespladib may reduce the harmful effects of snake venom, but its effectiveness in patients remains uncertain. We conducted a randomized, placebo-controlled clinical trial in India and the United States to evaluate intravenous followed by oral varespladib as a late adjunctive treatment given in addition to standard care, including antivenom. Outcomes were analyzed in 139 patients with snakebite envenoming. Study drug began, on average, more than 7 hours after the bite and in all cases after treatment with antivenom. Varespladib was generally safe and well tolerated but did not improve the trial’s prespecified primary outcomes. These findings suggest that adjunctive varespladib does not provide an overall benefit when initiated several hours after snakebite and after antivenom administration. The study provides information to guide future research on direct toxin inhibitors for snakebite.