Varespladib Misses Phase 2 BRAVIO Primary Endpoints but Shows Signals in Krait and Copperhead Snakebite

Ophirex’s varespladib did not meet the prespecified primary endpoints in the Phase 2 BRAVIO trial (NCT05717062), a randomized, double-blind, placebo-controlled study evaluating the drug alongside standard snakebite treatment. Published September 21, 2026, in PLOS Neglected Tropical Diseases, the study randomized 140 patients across 18 sites in India and the United States, with 139 included in the efficacy analysis.

All patients received standard care, including antivenom when clinically indicated. Varespladib was initiated a mean 7.3 hours after the snakebite and about 3.3 hours after antivenom, meaning BRAVIO primarily evaluated late adjunctive treatment rather than early toxin inhibition.

Varespladib targets a major venom toxin

Varespladib is a small-molecule inhibitor of secretory phospholipase A2 (sPLA2), a toxin family present in the venom of at least 95% of venomous snake species worldwide. sPLA2 toxins can contribute to tissue injury, inflammation and neuromuscular toxicity. Their small molecular size also provides a rationale for targeting venom toxins that may already have distributed into tissues, where antibody-based antivenoms have limited penetration.

In BRAVIO, adults received intravenous varespladib sodium at 0.45 mg/kg/hour for six hours, followed by a 500 mg oral loading dose and 250 mg twice daily for seven days when clinically able to take oral treatment.

Primary endpoints were not met

For elapid envenoming, the primary endpoint was time to recovery of a five-second head lift. The adjusted mean was 27.6 hours with varespladib versus 36.2 hours with placebo, but the difference was not statistically significant (p=0.6).

For viper envenoming, the primary endpoint was the Day 14 area under the curve (AUC) for a three-item Snakebite Severity Score. The adjusted mean AUC was 660 with varespladib versus 629 with placebo (p=0.7). Neither component reached statistical significance, so the global primary endpoint was not tested.

Krait and copperhead findings warrant further study

The study identified potentially important signals in specific snake types. Among 46 patients with elapid bites, including 24 treated with varespladib, Day 7 illness severity was 36% lower with varespladib. Among intubated patients, mean duration of mechanical ventilation was 21 hours versus 40 hours with placebo.

Among 24 copperhead-bite patients, varespladib was associated with a 43% lower point estimate for illness severity over 14 days, with a nominal p value of 0.04.

These findings should be considered hypothesis-generating rather than confirmatory. The krait and copperhead analyses involved relatively small patient populations, and the overall trial did not meet its prespecified primary endpoints. The investigators noted that the signals nevertheless merit further evaluation because they appeared across clinically relevant outcomes and are biologically consistent with the known sPLA2-mediated toxicities of these snake species.

Safety profile supports continued development

Varespladib was generally well tolerated. No deaths or serious adverse events occurred among varespladib-treated patients. Treatment-emergent adverse events occurred in 26% of the varespladib group and 30% of the placebo group, while potentially treatment-related events occurred in 4% and 11%, respectively.

FDA Animal Rule addresses the early-treatment challenge

The central development question now is whether varespladib can provide greater benefit when administered much earlier after envenomation, potentially before patients reach a hospital and receive antivenom.

BRAVIO could not directly answer that question because study drug administration occurred more than seven hours after the bite on average and generally followed antivenom. The investigators therefore noted that the results do not establish the efficacy of prehospital or pre-referral treatment.

Ophirex is continuing development under the FDA Animal Rule, a regulatory pathway applicable when human efficacy studies are not feasible or ethical under the intended treatment conditions. Rather than relying on another conventional hospital-based efficacy trial that could again introduce substantial treatment delays, the program will use adequate and well-controlled animal efficacy studies to evaluate the effects of earlier sPLA2 inhibition, particularly on survival and severe venom toxicity.

The company plans additional analyses of the krait and copperhead subgroups. The broader development strategy is to determine whether oral varespladib can function as an early rescue treatment after a snakebite, followed by antivenom once medical care becomes available, rather than replacing antivenom.

Reference

Ophirex Publishes Data from Phase 2 BRAVIO Trial Evaluating Intravenous Followed by Oral Varespladib for Snakebite, Ophirex, 22 September 2026

Broad-spectrum Rapid Antidote: Varespladib IV to Oral Trial for Snakebite (BRAVIO) (BRAVIO), ClinicalTrials.gov ID NCT05717062

Gerardo CJ, Bhalla A, Mohanty CR, Sahu BK, Kumar S, Agrawal S, et al. (2026) Adjunctive Varespladib after antivenom administration for snakebite: A phase II randomized clinical trial. PLoS Negl Trop Dis 20(9): e0014736. https://doi.org/10.1371/journal.pntd.0014736