FDA Approves First-Ever Antivenom for Scorpion Stings

Nancy A. Melville Authors and Disclosures

August 4, 2011 (Tucson, Arizona) The US Food and Drug Administration (FDA) for the first time yesterday approved an antivenom specifically for the treatment of Centruroides scorpion stings. "This is an historic event," Leslie Boyer, MD, lead investigator on the antivenom's clinical trials, said in a press statemen t. "This is the first-ever drug approved for this use by the FDA; the first -ever drug that we are awa re of being developed fully in Latin America and subsequently approved by the FDA; the first -ever scorpion antivenom proved effective under controlled clinical trials; and the first -ever antivenom with so few allergic reactions." Clinical trials have demonstrated the product, called Anascorp, to be capable of rapidly reversing the symptoms of scorpion envenomation, which can be particularly dangerous to children and include fluid in the lungs, breathing problems, excess saliva, blurred vision, slurred speec h, trouble swallowing, abnormal eye movements, and muscle twitching. The injectable antivenom, produced in Mexico by Instituto Bioclon and licensed in the United States by Rare Disease Therapeutics of Franklin, Tennessee, is made from the plasma of horses immunized with scorpion venom. It targets scorpion venom that is toxic to the nerves. "Ninety-eight percent of children treated with this drug have their symptoms from scorpion stings resolved in less than 4 hours," Dr. Boyer said during a press briefing h ere yesterday. "Historically, chart records of the same types of patients showed that 98% of children were still sick and still needing intensive care if they were admitted before the antivenom was available. A record like that is just about as strong as a new drug can have," said Dr. Boyer, who is director of the University of Arizona's Venom Immunochemistry, Pharmacology and Emergency Response (VIPER) Institute at the College of Medicine in Tucson. The efficacy of Anascorp, Centruroides (Scorpion) Immune F(ab)2 (Equine) Injection, was demonstrated in a randomized, double-blind, placebo-controlled trial of 15 children experiencing the neurologic signs of scorpion stings. In the study, the symptoms resolved within 4 hours among all 8 patients who received th e antivenom but in only 1 of the patients who received the placebo. In addition, safety and efficacy data for the FDA approval were collected from 1534 patients in open -label and blinded studies conducted over 12 years at a consortium of 27 hospitals in Ar izona and Nevada. Study sites ranged from urban medical centers to rural settings, where stings can be more common and sometimes require a costly airlift to a regional hospital with pediatric intensive care. "We did a follow-up study at San Carlos Indian Health Center that proved that we could use this treatment in a small town setting and treat patients just as well as if they'd been in an intensive care in Tucson, Arizona," Dr. Boyer said. The most common adverse effects observed with the treatment includ ed vomiting, fever, rash, nausea, itchiness, headache, runny nose, and muscle pain; these were experienced in only about 1% of cases. In the United States, the majority of scorpion stings occur in Arizona, where about 8000 stings occur each year. Several hundred of those, usually only from the particularly venomous bark scorpion, require medical treatment, and children are the most vulnerable to the stings, explained Andreas A. Theodorou, MD, chief of the Division of Pediatrics at the University of Arizona, at the press briefing. "A child who has been stung loses control of their body in such a way that it can be almost like a violent convulsion, and it can be extremely stressful for parents to witness the reaction," he explained. "As clinicians, we are very concerned that the breathing is affected in a discoordinative way, they have secretions that they can't handle, their lungs fill with fluid, and they may need to be placed on ventilators. So this is a critical state and a v ery dangerous situation." No Sedation Before the introduction of the antivenom, children were treated with a substantial amount of sedation. "A fraction of that amount of sedation would allow an adult to be sedated enough for surgery, but even the excessive am ount we had to use on these kids barely kept them in the bed," Dr. Theodorou explained.

"Now, when a child comes in with scorpion sting symptoms, we infuse the drug and 4 hours later the symptoms have subsided and the child can go home. The difference is phenomenal." Dr. Boyer added that the new treatment does not even include sedation. "There's no sedative component with this at all," she told Medscape Medical News. "Antibodies go straight to their target and that's it. We used to have to hold children in the ICU [intensive care unit] for days even after the antivenom wore off because they had basically been overdosed on sedation and we had to wait for that to clear the system." While Anascorp is the first FDA-approved scorpion antivenom, it isn't the first to be investigated in the United States. Significant progress was made on a prior antivenom treatment developed using goat serum at Arizona State University in the 1990s, but development was abruptly halted when the researcher on the drug retired. Dr. Boyer became involved in the effort to find a replacement while accompanying a National Geographic crew filing venomous creatures in Mexico in 1999. "We knew that we had only 250 stings a year in the US that were dangerous enough to require treatment with an tivenom, but in Mexico, they had 250,000 a year," she explained. That's largely because the vast geographic area in North America where scorpions thrive is in Mexico, with Arizona and a narrow slice of Nevada representing only the most northern reaches of the scorpion habitat, she explained. Dr. Boyer discovered that researchers at the Cuernavaca campus of the National Autonomous University of Mexico were investigating the effects of the new antivenom, but that they needed support in conducting the clinical trials that would be necessary in demonstrating safety and efficacy. "We discovered we needed each other as partners in a major collaboration that would use their biotechnology and science together with our translational medical technology and ability to do medical studies." The antivenom, which has been available in Mexico since the 1990s, must be administered by a physician and will usually be used in hospital emergency rooms. The product is expected to be available commercially in about a month. Dr. Boyer received grants from the FDA and State of Arizona for her research and has disclosed no relevant financial relationships. Instituto Bioclon provided the antivenom for the research.

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UA Research, Collaborative Efforts on Scorpion Antivenom Lead to FDA Approval First FDA approval for scorpion antivenom
TUCSON, Ariz. -- The U.S. Food and Drug Administration today approved Anascorp, an antivenom produced in Mexico and tested in clinical trials conducted through the University of Arizona, for use in treating patients suffering the effects of scorpion sting. This is an historic event, says Leslie Boyer, MD, director of the UAs VIPER (Venom Immunochemistry, Pharmacology and Emergency Response) Institute and lead investigator on the clinical trials. This is the first-ever drug approved for this use by the FDA; the first-ever drug that we are aware of being developed fully in Latin America and subsequently approved by the FDA; the first-ever scorpion antivenom proved effective under controlled clinical trials; and the first-ever antivenom with so few allergic reactions. This approval also is the culmination of a nearly 12-year collaboration of academic and clinical researchers with partners in business and industry from both sides of the border. Together with Dr. Boyer, a pediatrician and toxicologist at the UA College of Medicine, these entities joined forces to meet a critical and urgent need.

In Arizona, which has the highest concentration of dangerous bark scorpions in the United States, about 8,000 scorpion stings occur each year. Several hundred of these result in serious nerve poisoning and require medical treatment. Nearly all of these patients are young children, whose breathing may be severely affected by the effects of the venom. Without antivenom, children stung by scorpions typically require heavy sedation and intensive supportive care and, often, a ventilator. Decades ago, Arizonans had access to a different kind of antivenom that was produced at Arizona State University, but in 1999 the researchers approaching retirement put an end to new production. No known replacement existed, and the critical need for antivenom was about to become urgent. It was about this time that a chance meeting with a National Geographic television crew that was studying venomous creatures of Mexico led Dr. Boyer to visit the Cuernavaca campus of the UNAM (National Autonomous University of Mexico), home of the Institute of Biotechnology, where researchers were investigating the effects of a new antivenom made by Instituto Bioclon, based in Mexico City. She soon determined to bring that antivenom to Arizona. Having witnessed the use of the antivenom in children stung by scorpions in Mexico, Dr. Boyer was certain of the potential for this drug to help children in Arizona. But the safety and efficacy of the product had to be proved to the exacting standards of the FDA. With a grant from the Office of Orphan Products Development of the FDA, a team of UA and UNAM faculty conducted a study of the then-investigational drug in 2004 and 2005 at University Medical Center and Tucson Medical Center in Tucson. The results were dramatic. Recounted in the New England Journal of Medicine, the study showed that the antivenom alleviated the symptoms of nerve poisoning in children following a scorpion sting in a very short time. It also reduced the need for sedative medication dramatically and lowered levels of scorpion venom in the bloodstream. A second study, conducted primarily at the San Carlos Hospital on Arizonas San Carlos Apache Indian Reservation, confirmed these findings and demonstrated that the treatment could be safely provided in a rural hospital, far from pediatric intensive care. Andreas Theodorou, MD, a UA professor of pediatrics, chief medical officer of University Medical Center and a member of the research team, says, This antivenom basically takes symptoms away in a very short time. What was a life-threatening disease that would put kids in the pediatric ICU has become, for most of them, an outpatient disease. In 2004, the state of Arizona supplied additional research funds through the Arizona Department of Health Services and the Arizona Biomedical Research Commission, enabling the UA to expand its study. Instituto Bioclon and U.S. partner Rare Disease Therapeutics, Inc., of Tennessee agreed to provide the antivenom to qualifying hospitals, while preparing a formal license application to the U.S. FDA. Since then, nearly 2,000 patients in Arizona and Nevada have received the antivenom. Ultimately, these clinical trials brought together 27 Arizona hospitals, one hospital in Nevada and hundreds of volunteer health-care professionals, creating a first-of-its-kind outreach study network capable of conducting clinical trials of a treatment for a rare emergency.

The benefits of this cooperative, international effort extend beyond U.S. patients. Alejandro Alagn, MD, PhD, from the Institute of Biotechnology of the UNAM, is an antivenom researcher and adviser to Instituto Bioclon. He notes that this work has helped patients in Mexico, too: We have been working together to test the Mexican antivenom under United States rules for close to 12 years, learning a lot from the process and learning from each other. This collaboration has really helped us produce a better product. For this project we needed to combine laboratory science, clinical science and a good manufacturer, and we needed to design a good clinical trial. During the course of the clinical trials, support provided by the UNAM included developing new analytical techniques to measure the venom and antivenom in the blood of Arizona patients. In addition, scientists from the UNAM worked closely with the Bioclon Institute to ensure that manufacturing processes met the U.S. standards. This collaboration among academic and business partners also is poised to have a global impact. The research has attracted attention from numerous countries with venomous creatures that pose problems for people. Among these is Morocco, where Bioclon, assisted by Drs. Boyer and Alagn, plans to begin clinical trials on a similar antivenom to treat stings inflicted by North Africas deadly scorpions. This project owes its success to the hard work and participation of thousands of people, Dr. Boyer says. The consortium includes representatives of numerous state and federal agencies; multiple colleges and departments at the UA; 27 Arizona hospitals and one in Nevada; three poison control centers including the UAs Arizona Poison and Drug Information Center, which once housed the VIPER Institute; nearly 2,000 Arizona families; undergraduate students and graduate students on both sides of the border; ranchers and scorpion hunters; businessmen and factory workers; and academic colleagues on four continents. All played significant roles, Dr. Boyer explains, adding, The vast majority of these dedicated individuals received no compensation. They did it because it was in the best interest of the children, because it was the right thing to do.