Varespladib in the Treatment of Snakebite Envenoming: Development History and Preclinical Evidence Supporting Advancement to Clinical Trials in Patients Bitten by Venomous Snakes

Abstract

The availability of effective, reliably accessible, and affordable treatments for snakebite envenoming is a critical and long unmet medical need. Recently, small, synthetic toxin-specific inhibitors with oral bioavailability used in conjunction with antivenom have been identified as having the potential to greatly improve outcomes after snakebite. Varespladib, a small, synthetic molecule that broadly and potently inhibits secreted phospholipase A2 (sPLA2s) venom toxins has renewed interest in this class of inhibitors due to its potential utility in the treatment of snakebite envenoming. The development of varespladib and its oral dosage form, varespladib-methyl, has been accelerated by previous clinical development campaigns to treat non-envenoming conditions related to ulcerative colitis, rheumatoid arthritis, asthma, sepsis, and acute coronary syndrome. To date, twenty-nine clinical studies evaluating the safety, pharmacokinetics (PK), and efficacy of varespladib for non-snakebite envenoming conditions have been completed in more than 4600 human subjects, and the drugs were generally well-tolerated and considered safe for use in humans. Since 2016, more than 30 publications describing the structure, function, and efficacy of varespladib have directly addressed its potential for the treatment of snakebite. This review summarizes preclinical findings and outlines the scientific support, the potential limitations, and the next steps in the development of varespladib's use as a snakebite treatment, which is now in Phase 2 human clinical trials in the United States and India.

Keywords: ASV; LY315920; LY333013; antivenom; inhibitor; preclinical; varespladib.

Figure 1

Chemical and structural descriptions of (A) varespladib-sodium (API) and (B) varespladib-methyl. Circles denote the distinguishing features of the API, a sodium salt and the prodrug, varespladib-methyl which is esterified to facilitate passage through the stomach prior to conversion to the API, varespladib-Na⁺.

Figure 2

Varespladib-methyl (LY333013) administered following the onset of systemic envenoming signs corrected the anticoagulant effect of M. fulvius venom in porcine blood (A,B). The anticoagulant and hemolytic effects (C) often preceded neurological deficits in this study. Others have provided deeper insights into the mechanisms by which Micrurus sPLA2 from different regions and in different animals cause more or fewer anticoagulant effects as well as hemolysis. Adapted with permission from Lewin et al. 2018.

Figure 3

Crystallographic studies examining both the venom sPLA2 and the sPLA2-like toxins from B. moojeni demonstrate the binding of varespladib to the hydrophobic channels of these important toxins. MjTx-II in grey (top right with varespladib represented as magenta sticks) and MjTx-I (bottom left, with varespladib represented by yellow sticks) are shown superposed on the bottom right. Arrow point to varespladib bound to the active site [22].