318 LY333013: A Candidate First-in-Class, Broad Spectrum, Oral Field Antidote to Snakebite with Curative Potential

Snakebite is a newly designated WHO, Class A, Neglected Tropical Disease. 75% of the nearly 100,000 annual deaths by snakebite occur in the out-of-hospital setting. 98% of snakebite victims and their livestock reside in impoverished communities. Antivenom is the only existing treatment for snakebite but requires hospital administration. A potent, broad-spectrum, heat stable, oral antidote to snakebite could address many of the limitations of antivenom and is desirable for improved outcomes, access to care, and for those whose occupation puts them at risk for snakebite in diverse settings (eg, military personnel and their working canines). We previously identified a small molecule with characteristics meeting criteria for a field antidote. LY315920, the parent compound of LY333013 inhibited more than 25 different snake venom sPLA2s from 6 continents (Lewin et al 2016). Our objective was to determine the efficacy of an orally bioavailable, broad-spectrum sPLA2 inhibitor to rescue mice and pigs in an experimental model of lethal envenomation. Mice and/or juvenile pigs were envenomed with 100% lethal doses of whole venom from medically important snakes (eg, coral snake (M. fulvius), saw-scale viper (E. carinatus), Russell's viper (D. russelli), Mojave rattlesnake (C. scutulatus), neotropical rattlesnake (C. durissus terrificus), coastal taipan (O. scutellatus)) and then treated orally with 1 or multiple doses of LY333013 at various time points following experimental envenomation (range 1 minute to 2.5 hours depending on experiment). 98% of treated mice (N=49/50) and outlived carrier (control, N=32). The mice were observed for a minimum of 24 hours 100% of pigs survived to 96 hour endpoint (N=5) with most requiring q6 hour oral antidote for the first 24 hours. All controls died within 8 hours. Two doses of drug were required to cure mice injected with E. carinatus sochureki, D. russelli, C. durissus terrificus, and O. scutellatus when drug was administered with an hour delay or more. For taipan, a single dose of oral drug given within 10 minutes was uniformly curative. Figure 1 shows 24 hour K-M in mice given single dose (10mg/kg) LY333013 orally within 30 minutes of experimental envenomation with coastal taipan venom. LY333013 appears to have broad efficacy in animal models and can reverse neuromuscular paralysis even after onset of symptoms. Pre-clinical studies with experimental envenomation and its safety record in multiple Phase 1 and Phase 2 human clinical trials for other indications suggest it could be part of a solution to the global burden of disease caused by snakebite. Further exploration of its development as a field antidote and adjunct to antivenom is warranted.