Snakes, says Dr. Matt Lewin, are “like little mobile landmines”: They’re invisible, lying in wait in populated areas, killing or maiming without warning. Worldwide, tens of thousands of people die from snakebites every year.
But an existing drug could change that. Lewin, an emergency medical doctor, presented findings Friday that a compound called varespladib can counteract the effects of 28 common venoms in biochemical models — making it the closest thing yet to a universal antidote.
“Antidote” is the key word here. Hospitals in tropical regions are stocked with antivenoms, which are snake-specific and usually require refrigeration and doctors to administer them. Antidotes, however — broadly effective, heat-stable compounds that interfere with the biochemical pathways causing the problems — are fewer and no universal one yet exists.
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Part of the difficulty in developing them is that snakes kill in different ways. Snake venom can paralyze, cause excessive clotting or bleeding, eat away at tissues, or a combination of all three. A truly effective antidote would battle all of that deadly biochemistry.
Since 2011, Lewin, who is director of the Center for Exploration and Travel Health at the California Academy of Sciences, has been on a quest to find such a drug, which a non-expert victim could deploy in the field against a variety of snakes. He has narrowed in on an enzyme in the phospholipase A2 family, called sPLA2, which is produced by the body during inflammation and is also a component of snake venom. Studies have shown that sPLA2 in venom can damage the nervous system, muscles, and blood cells.
To find a molecule that battled sPLA2, Lewin scoured the literature for substances that had already been tested in clinical trials for other conditions. He created a list of thousands of compounds that he thought might do the job, and then maxed out his personal credit card buying them and getting ready for the tests.
Using a commercially available sPLA2 test, Lewin mixed venom and antidote and measured sPLA2 by way of a color indicator. In these tests, one drug clearly stood out: Varespladib, an inhibitor of sPLA2 originally developed by Eli Lilly and Shinogi to combat sepsis.
Lewin sent his methods to the Yale Center for Molecular Discovery in West Haven, Conn., and asked researcher Janie Merkel to replicate the tests on a larger variety of venoms, including those from black mamba, Russell’s viper, Indian cobra, Cape cobra, krait, Coastal taipan, Eastern coral snake, South American rattlesnake, and banded sea krait. The drug incapacitated sPLA2 in all 28 venoms tested.
Then Lewin turned to rodent studies, hiring a contract research organization to give rodents a lethal dose of coral snake or common adder venom. The 17 animals that got Varespladib one minute or five minutes after injection all were alive after 24 hours. Those not given the antidote all died within eight hours. The dead rodents had high levels of sPLA2, while the treated animals’ levels hardly rose above baseline.
Those findings, presented at Venom Week at East Carolina University in Greenville, N.C., haven’t been published or peer reviewed yet, but Lewin took them straightaway to potential funders. “From that point, it was easy to raise money,” Lewin said. He formed a startup called Ophirex to develop and test the drug, and its oral formulation, varespladib methyl. Family and friends provided seed money.
Others in the field are excited by the developments but caution that the days are still early ones — which no one is more cognizant of than Lewin, who qualifies many statements with, “No lives have been saved yet!”
“The results I have seen are very interesting and promising,” said José María Gutiérrez of the University of Costa Rica, who has been researching snake venom and treatments for 40 years and has seen Lewin’s results. But, he noted, it’s not quite time to make the giant leap toward human trials. He believes the work should progress with further animal studies. “The rationale of this approach is sound and should be pursued by researchers at the experimental and clinical levels,” he said.
Varespladib would likely be safe at doses to treat snakebite, though a 2014 study found it increased people’s risk of heart attack if taken daily. Lewin’s team is writing up the results for peer-reviewed publication, and have submitted a patent application that would allow them to develop Varespladib specifically for use against snakebites. This is called “drug repositioning,” in which new rights are issued if the new company changes the formulation, delivery mechanism, or utility.
Lewin and his collaborators will now work toward a human trial. And if that works, he plans to deploy the compound in the real world. “For me, this can’t move fast enough,” he said. “But safety is the first concern.”