Adjunctive Varespladib after antivenom administration for snakebite: A phase II randomized clinical trial

@article{gerardo2026adjunctive,
  title = {{Adjunctive Varespladib after antivenom administration for snakebite: A phase II randomized clinical trial}},
  author = {Charles J. Gerardo and Ashish Bhalla and Chitta R. Mohanty and Badal K. Sahu and Surendra Kumar and Suneil Agrawal and Manu Ayyan S and Eileen Shu and Travis Deuson and Madhu Kumar R and Norman L. Beatty and Peter D. Akpunonu and Farshad M. Shirazi and Sarah Watkins and Anne-Michelle Ruha and Shawn M. Varney and Anil K. Goel and Medhavi Gautam and Justin Arnold and Chanaveerappa Bammigatti and Samuel J. Francis and Suresh Selvam and Harish Kumar and Adiel Aizenberg and Andrew Micciche and Rylee S. Bledsoe and Ginger Boatright and Suraj C. Oomman and Stephen P. Samuel and Janet T. Wittes and Rebecca W. Carter and Matthew R. Lewin and Timothy F. Platts-Mills},
  journal = {PLOS Neglected Tropical Diseases},
  year = {2026},
  month = sep,
  doi = {10.1371/journal.pntd.0014736},
  url = {https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014736},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - Adjunctive Varespladib after antivenom administration for snakebite: A phase II randomized clinical trial
AU  - Charles J. Gerardo
AU  - Ashish Bhalla
AU  - Chitta R. Mohanty
AU  - Badal K. Sahu
AU  - Surendra Kumar
AU  - Suneil Agrawal
AU  - Manu Ayyan S
AU  - Eileen Shu
AU  - Travis Deuson
AU  - Madhu Kumar R
AU  - Norman L. Beatty
AU  - Peter D. Akpunonu
AU  - Farshad M. Shirazi
AU  - Sarah Watkins
AU  - Anne-Michelle Ruha
AU  - Shawn M. Varney
AU  - Anil K. Goel
AU  - Medhavi Gautam
AU  - Justin Arnold
AU  - Chanaveerappa Bammigatti
AU  - Samuel J. Francis
AU  - Suresh Selvam
AU  - Harish Kumar
AU  - Adiel Aizenberg
AU  - Andrew Micciche
AU  - Rylee S. Bledsoe
AU  - Ginger Boatright
AU  - Suraj C. Oomman
AU  - Stephen P. Samuel
AU  - Janet T. Wittes
AU  - Rebecca W. Carter
AU  - Matthew R. Lewin
AU  - Timothy F. Platts-Mills
PY  - 2026
DA  - 2026/09/21
JO  - PLOS Neglected Tropical Diseases
DO  - 10.1371/journal.pntd.0014736
UR  - https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014736
AB  - Background: Snakebite envenoming causes an estimated 81,000–138,000 deaths and more than 400,000 cases of permanent disability each year, disproportionately affecting low-resource regions. Antivenom is the only approved 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, both in addition to standard of care including antivenom. 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 3rd, 2023, and October 19th, 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 with varespladib vs. 629 with 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, late adjunctive varespladib did not meet the primary endpoint. Interpretation of these results is limited by heterogeneity in the snake species responsible for envenoming and the associated differences in venom composition, clinical manifestations, and antivenom treatments. Author summary: Snakebite envenoming causes an estimated 81,000–138,000 deaths and more than 400,000 cases of permanent 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 humans 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. Clinical interpretation of these findings in either India or the U.S. is limited by the wide range of snake species responsible and different antivenom products used. Safety results and findings from pre-specified subgroups defined by snake type provide information to guide future research on direct toxin inhibitors for snakebite.
SN  - 1935-2735
ER  -