Introduction: Snakebite is an urgent, unmet global medical need causing significant morbidity and mortality worldwide. Varespladib is a potent inhibitor of venom secretory phospholipase A₂ (sPLA₂) that can be administered orally via its prodrug, varespladib-methyl. Extensive preclinical data support clinical evaluation of varespladib as a treatment for snakebite envenoming (SBE). The protocol reported here was designed to evaluate varespladib-methyl for SBE from any snake species in multiple geographies. Methods and Analysis: BRAVO (Broad-spectrum Rapid Antidote: Varespladib Oral for snakebite) is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study to evaluate the safety, tolerability, and efficacy of oral varespladib-methyl plus standard of care (SoC) vs. SoC plus placebo in patients presenting with acute SBE by any venomous snake species. Male and female patients 5 years of age and older who meet eligibility criteria will be randomly assigned 1:1 to varespladib-methyl or placebo. The primary outcome is the Snakebite Severity Score (SSS) that has been modified for international use. This composite outcome is based on the sum of the pulmonary, cardiovascular, nervous, hematologic, and renal systems components of the updated SSS. Ethics and Dissemination: This protocol was submitted to regulatory authorities in India and the US. A Clinical Trial No Objection Certificate from the India Central Drugs Standard Control Organisation, Drug Controller General-India, and a Notice to Proceed from the US Food and Drug Administration have been obtained. The study protocol was approved by properly constituted, valid institutional review boards or ethics committees at each study site. This study is being conducted in compliance with the April 1996 ICH Guidance for Industry GCP E6, the Integrated Addendum to ICH E6 (R2) of November 2016, and the applicable regulations of the country in which the study is conducted. The trial is registered on Clinical trials.gov, NCT#04996264 and Clinical Trials Registry-India, 2021/07/045079 000062.

Introduction Snakebite envenoming (SBE) results in over 500 000 deaths or disabling injuries annually. Varespladib methyl, an oral inhibitor of secretory phospholipase A2, is a nearly ubiquitous component of snake venoms. We conducted a phase II clinical trial to assess efficacy and safety of oral varespladib methyl in patients bitten by venomous snakes. Methods This double-blind, randomised, placebo-controlled trial enrolled patients in emergency departments in India and the USA. Patients with SBE were randomly assigned (1:1) to receive varespladib methyl or placebo two times per day for 1 week. All patients received standard of care, including antivenom. The primary outcome was change in the composite Snakebite Severity Score (SSS) measuring the severity of envenoming, from baseline to the average composite SSS at 6 and 9 hours. Results Among 95 patients randomised August 2021 through November 2022, the most common snakebites were from Russell’s vipers (n=29), copperheads (n=18) and rattlesnakes (n=14). The SSS improved from baseline to the average at 6 and 9 hours by 1.1 (95% CI, 0.7 to 1.6) in the varespladib group versus 1.5 (95% CI, 1.0 to 2.0) in the placebo group (difference −0.4, 95% CI, −0.8 to 0.1, p=0.13). While key secondary outcomes were not statistically different by treatment group, benefit was seen in the prespecified subgroup initiating study drug within 5 hours of bite (n=37). For this early treatment group, clinically important differences were observed for illness severity over the first week, patient-reported function on days 3 and 7 and complete recovery. No death or treatment emergent serious adverse event occurred. Conclusion For emergency department treatment of snakebites, the addition of varespladib to antivenom did not find evidence of difference for the primary outcome based on the SSS. A potentially promising signal of benefit was observed in patients initiating treatment within 5 hours of snakebite.

Snakebite envenoming causes an estimated 138,000 deaths annually worldwide, with approximately 75% of fatalities occurring prior to arrival at definitive medical care. Even in regions where antivenom is available in hospitals, the absence of treatment options before a victim can reach definitive care results in delays of many hours before therapy is initiated. Manufacturing complexity, region-specific products, and the risk of anaphylaxis further limit the availability and use of antivenom in many regions. Reducing the persistently high mortality of snakebite envenoming requires both novel scientific approaches and partnerships that extend beyond traditional disciplinary and funding silos. This article describes the collaboration between Ophirex, a Public Benefit Corporation developing the oral secretory phospholipase A2 (sPLA2) inhibitor varespladib, and the United States military, which has identified a capability gap in snakebite treatment for forward-deployed personnel. The partnership was driven by a shared requirement for a shelf-stable, easy-to-administer, snake-species-agnostic therapy suitable for use prior to definitive medical care. A central insight of the program was that military operational requirements and global public health needs converged around the same product characteristics, enabling a strategically aligned development effort. From early proof-of-concept studies through regulatory pathway definition and advanced development, the Military–Ophirex partnership integrated operational requirements, regulatory planning, and iterative risk mitigation to advance manufacturing, nonclinical, and clinical development. This work provides both practical insights into complex drug development and a case study in how structured partnerships can carry innovation through translation in underfunded and operationally challenging conditions.