The BRAVO Clinical Study Protocol: Oral Varespladib for Inhibition of Secretory Phospholipase A2 in the Treatment of Snakebite Envenoming

Abstract

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.

Interactions of small molecule inhibitors with secreted phospholipase A2: A review of the structural data

“…Both drugs have entered various Phase II and III clinical trials for treatment of several inflammatory diseases; however, efficacy of these drugs have been limited thus far (Abraham et al., 2003; Bradley et al., 2005; Kearney & Naum, 1999; Nicholls et al., 2014). Most recently, these drugs have been repurposed and entered Phase II trials for treatment of snakebite envenomation (NCT04996264) (Carter et al., 2022) as well as COVID‐19‐associated acute respiratory distress syndrome (NCT04969991 – study was terminated). Shionogi also studied the inhibitory activity of various indolizine and indene derivatives (Hagishita et al., 1996).…”

Modulation of immunity by the secreted phospholipase A2 family

“…Beyond this caveat, varespladib has a striking survival benefit against snake bite as a result of the inhibition of venom sPLA 2 s 252,253 and is now under a preclinical trial. 254 As none of the current sPLA 2 inhibitors block sPLA 2 -III and…”

“…These observations provide rationale for pursuing two distinct therapeutic approaches targeting sPLA 2 : the use of an inhibitor or neutralizing antibody highly selective for a detrimental sPLA 2 or administration of a beneficial sPLA 2 or its key metabolite. Beyond this caveat, varespladib has a striking survival benefit against snake bite as a result of the inhibition of venom sPLA 2 s 252,253 and is now under a preclinical trial 254 …”

Ruthenium-based antivenom attenuates Crotalus atrox venom mediated coagulopathy in rabbits

“…Varespladib improves coagulopathy when combined with a metalloproteinase inhibitor [20]. A clinical trial has been proposed involving varespladib administration to improve envenomation outcomes [21]. These enterprises are laudable and it is hoped they will provide more optimized care of snake bite victims.…”