<img alt=“Bbasgen-bark-scorpion.jpg” src=“https://blogs.nature.com/nm/spoonful/Bbasgen-bark-scorpion.jpg” width=“300” height=“213” align=“right” hspace=“10px vspace=”8px">
The bark scorpion (Centruroides sculpturatus) can measure only 3 inches long and still pack a deadly sting. But this very small creature has met its match in a very small clinical trial. This week, the US Food and Drug Administration (FDA) approved the first drug that takes the sting out of scorpion-inflicted wounds based in large part on a study involving just15 subjects — eight of whom received the antivenom and seven who received placebo treatments.
The product, called Anascorp, is an antivenom made from the plasma of horses injected with venom from the scorpion. The tiny trial showed that Anascorp can reverse the progressive neurological paralysis — which leads to severe pain, extreme nausea, blurred vision and breathing problems, among other symptoms — in children stung by the predatory arachnids.
“It’s a rare, potentially fatal, emergency medical disease that predominantly affects rural children, and if you put all those adjectives together, it didn’t look possible to put [a placebo-controlled trial] together at all,” says Leslie Boyer, director of the Venom Immunochemistry, Pharmacology and Emergency Response (VIPER) Institute at the University of Arizona in Tucson, who led the supporting trial reported two years ago in the New England Journal of Medicine. “We started out with a daunting task.”
For one thing, trial investigators can’t enroll participants ahead of time because there’s no way of knowing who will get stung. Then there was the problem of getting hospitals to sign up to a placebo-controlled trial. Another antivenom, produced between 1965 and 2000 at Arizona State University’s Antivenom Production Laboratory in Phoenix, was already available at most hospitals in Arizona. Although this treatment was never approved by the FDA, it was made available free of charge and never crossed state lines, so it fell outside of the federal agency’s jurisdiction.
That antivenom had become the de facto standard of care in Arizona for decades, until production ceased in 2000 and supplies of the product started dwindling by the middle part of the last decade. The antivenom was also not highly purified, which meant it often led to anaphylactic reactions. But even so, few doctors, many of whom still had stockpiles of the old product, were unwilling to withhold the potentially life-saving treatment from children in order to conduct a proper placebo-controlled trial which was necessary to test Anascorp.
In the end, Boyer found just two hospitals in Tucson prepared to participate. Between May 2004 and October 2005, she and her colleagues treated 15 children as part of the trial, mostly under the age of six. Even with the small sample size, the results were striking: symptoms of the scorpion’s neurotoxin resolved within four hours for all eight children receiving Anascorp, whereas only one of seven subjects receiving placebo recovered so quickly. The rest received heavy doses of sedatives and had to stay for longer in intensive care units before it was deemed safe enough to discharge them from the hospitals.
Even before the trial investigators analyzed the results, however, they already had a suspicion of the antivenom’s overwhelming effectiveness. Boyer recalls physicians at the Tuscon hospitals telling her: “We want you to know that if you unblind this data and it’s as unequivocal as we think it is, we’ll never do [the trial] again.”
The scientists felt it was unethical to keep giving dummy shots, which made larger placebo-controlled trials impossible, notes Dorothy Scott, head of the Laboratory of Plasma Derivatives at the FDA’s Center for Biologics Evaluation and Research. “Once it became known among clinicians that the Anascorp was looking pretty good there, everyone wanted to use and it would have been very difficult to do any placebo-controlled trial after that,” she says. The findings were proving statistically significant already, and there was animal data to back up the antivenom’s neutralizing effect, she adds.
Still, the researchers needed to show that the drug was safe enough to roll out en masse across the Grand Canyon State. So, between 2004 and 2010 they launched an open-label trial where they made Anascorp available at more than 20 rural health centers across Arizona, where the majority of bark scorpions live. Only around 200 children in Arizona typically develop severe reactions to scorpion stings each year, and by the end of the open-label study, the researchers were treating all those children, and even some adults.
“We think we were capturing everyone who needs that drug — and probably more,” says Jude McNally, medical science liaison at Rare Disease Therapeutics, a Tennessee-based biotech that licensed the drug from Mexico’s Bioclon Institute. “In time, it became clear we had done the largest number of any antivenom study in history,” adds Boyer. “We had such a black and white result that after time it was silly to go on.” Eventually, more than 1,500 people, the majority of whom were children, took the drug with only mild side effects. That data also formed part of the FDA application.
Boyer is now working with researchers from the Moroccan Poison Control and Pharmacovigilance Center to test a different antivenom targeting the neurotoxins of a different scorpion at rural hospitals across the North African country — and she is advising her colleagues to launch a placebo-controlled trial. “It’s the only way I know how to get a statistically valid result out of a tiny, tiny population,” she says.
Image: Wikipedia/Musides