Snake Bites

Efficacy signal observed in subgroup of victims treated within five hours of bite reinforces critical importance of timely treatment and need for a field therapy that could improve patient outcomes Globally, 75% of deaths from venomous snakebites occur before the victim can reach appropriately-equipped medical care CORTE MADERA, Calif.--(BUSINESS WIRE)--Ophirex, Inc., a Public Benefit Corporation developing an oral treatment to address the unmet medical needs of snakebite victims globally, today announced that BMJ Global Health has published data from the company’s BRAVO trial evaluating oral varespladib. Varespladib is a small synthetic molecule that directly inhibits secretory phospholipase A2 (sPLA2), an enzyme that is present in more than 95% of all snake venoms. The oral form is being developed as an early intervention treatment for patients and has potential to be the first-ever field therapy for snakebite envenoming, providing treatment at “time-of-bite.” The article in BMJ Global Health details results from BRAVO (Broad-spectrum Rapid Antidote: Varespladib Oral for snakebite), a multi-center, randomized, double-blind, placebo-controlled, Phase 2 study designed to evaluate the safety, tolerability and efficacy of oral varespladib. It enrolled 95 patients in the U.S. and India who were administered either varespladib or placebo in conjunction with the standard of care, which included antivenom in 93 of the 95 patients. “The BRAVO trial set out to do something no one has done before. In addition to being the first study to evaluate a direct toxin inhibitor for the treatment of snakebites, BRAVO was the first clinical trial to enroll patients bitten by any species of snake across two continents, including some of the world’s deadliest species,” said Timothy Platts-Mills, M.D., MSc, Chief Medical Officer of Ophirex. “While this Phase 2 study did not meet its primary endpoint, a promising signal of benefit was seen in the group of patients receiving treatment within five hours of a bite, reinforcing varespladib’s potential as an early treatment option and suggesting initial utility as a field treatment.” For the early treatment subgroup, clinically important differences were observed across important outcomes, such as lower illness severity over the first week, higher rates of complete recovery, and improved patient-reported function in patients receiving varespladib. Results from the BRAVO trial also suggest that varespladib is safe and well tolerated for the treatment of snakebite, adding to a robust body of safety data for this therapeutic candidate. “Antivenom, the current standard of care for snakebites, has several limitations, including the need to match antivenom to specific snake types, the risk of anaphylaxis, and the need to be administered intravenously in a medical setting. Yet we know that 75% of deaths due to venomous snakebites occur before the victim ever reaches the hospital. Even in those patients who survive, early treatment leads to better outcomes,” said Charles J. Gerardo, M.D., Professor and Chair for the Department of Emergency Medicine at Duke University and BRAVO trial investigator. “These data represent an encouraging advancement for patients bitten by snakes with the potential to fill a significant unmet need as a real world, early treatment before a patient reaches a healthcare facility.” “India has the greatest snakebite burden in the world, and 97% of snakebite deaths in the country occur in rural areas far from medical care and current treatments. A novel therapeutic molecule such as oral varespladib in addition to standard of care has the potential to enable treatment at the time of bite or en route to a more advanced facility and could be an important improvement in care for patients and medical systems alike,” said Dr. Suneetha D.K., Professor and Head of Internal Medicine, Mysore Medical College and Research Institute, Mysuru and a BRAVO trial investigator. “These findings support Ophirex’s vision to advance varespladib initially as an oral field treatment available at the time of the bite. We look forward to applying key learnings from this clinical trial to ongoing studies that address the long unmet need for a field treatment,” said Matthew R. Lewin, MD, PhD, Chief Scientific Officer and Founder of Ophirex, who first published the concept of this molecule as a field treatment in snakebite in 2016. The manuscript, titled “Oral Varespladib for the Treatment of Snakebite Envenoming in India and the United States (BRAVO): A Phase 2 Randomised Clinical Trial,” is available online here . About Ophirex Ophirex is a Delaware Public Benefit Corporation developing a first-of-its-kind oral treatment to address the global unmet need of venomous snakebites. Worldwide, there are approximately 500,000 cases of snakebite envenoming resulting in death or permanent disability each year. While antivenom has been the standard of care to treat these bites for more than 100 years, it can only be administered in a hospital setting. This poses a significant challenge as 75% of deaths from venomous snakebites occur before the victim can reach appropriately equipped medical care. Ophirex is advancing its investigational treatment, varespladib, as a broad-spectrum treatment for snakebite in both oral and intravenous formulations with human and veterinary applications. Ideally taken immediately following a bite, it is intended to provide a bridge to survival between bite and arrival to the hospital. If successful, this early intervention is anticipated to result in improved overall outcomes for patients at risk of death and long-term disability from snakebite. The company has presented some of the BRAVO data at scientific conferences. Ophirex is concluding a separate Phase 2 study to evaluate IV-to-oral dosing of varespladib for snakebite envenoming based on learnings from BRAVO. For more information, visit . Contacts Media Contact: Emma Yang Health+Commerce emma@healthandcommerce.com 908-391-7197

Scientists have discovered a new snakebite treatment to prevent the devastating tissue damage caused by African spitting cobra venom. Spitting cobra venom is incredibly potent and causes dermonecrosis, which presents as rapid destruction of skin, muscle and bone around the site of the snakebite, and can lead to permanent injuries and disfigurements, including limb loss and amputations in extreme cases. Using the repurposed small molecule drug varespladib to block one of the two major dermonecrosis-causing toxins in spitting cobra venom prevents skin and muscle damage. Each year, it is estimated that snakebite causes long term detrimental effects in around 400,000 people across the world, with a substantial proportion of those in Africa the result of spitting cobra bites. Scientists have discovered a groundbreaking new snakebite treatment to prevent the devastating tissue damage caused by African spitting cobra venom. Spitting cobra venom is incredibly potent and causes dermonecrosis, which presents as rapid destruction of skin, muscle and bone around the site of the snakebite, and can lead to permanent injuries and disfigurements, including limb loss and amputations in extreme cases. Professor Nicholas Casewell and Liverpool School of Tropical Medicine colleagues including Dr Steven Hall -- who is now at Lancaster University- discovered that using the repurposed small molecule drug varespladib to block one of the two major dermonecrosis-causing toxins in spitting cobra venom prevents skin and muscle damage. Each year, it is estimated that snakebite causes long term detrimental effects in around 400,000 people across the world, with a substantial proportion of those in Africa the result of spitting cobra bites. Currently, there is no effective treatment for tackling severe local envenoming caused by spitting cobra venom. Existing antivenoms only work on bites by other snake species and are often ineffective for treating local envenoming because antivenom antibodies are too large to effectively penetrate into the region around the bite site. Professor Nicholas Casewell of LSTM said: "Our findings hold much promise to improve the treatment of tropical snakebite. Current treatments for spitting cobra bites are widely regarded as being ineffective, meaning that rates of disability and amputation have remained high across much of Africa. Our data shows that blocking just one of the main toxin families in spitting cobra venom will likely prevent the debilitating tissue damage seen in thousands of snakebite patients each year." Professor Casewell's team, led by PhD student Keirah Bartlett and Dr Steven Hall, then of LSTM and now at Lancaster University, and also involving researchers from Canada, Denmark, Costa Rica and the USA, first analysed spitting cobra venom to identify the toxins responsible for causing venom-induced dermonecrosis. The results showed that cytotoxic three-finger toxins (CTx) are largely responsible but that phospholipases A2 (PLA2) toxins play a critical role in the process. Local injection of the PLA2-inhibiting drug varespladib reduced the extent of dermonecrosis, even when delivered up to an hour after the venom, and the protection conferred by the drug also extended to venom-induced muscle toxicity. According to the authors, the findings suggest that varespladib could become an invaluable treatment against the tissue-damaging effects of black-necked and red spitting cobra venoms, which cause extensive morbidity in snakebite victims across the African continent. Lead author Keirah Bartlett said: "These findings are extremely promising, not only does this offer up a new mode of treatment where previously nothing effective existed, but because varespladib has already gone through testing in human clinical trials, including for snakebite, it could be available for use in real world patients very soon." Dr Hall added: "Snakebite is a devastating neglected tropical disease, with tissue destruction caused by necrotic snake venoms permanently injuring hundreds of thousands of victims every year. Our work shows that the repurposed drug, Varespladib, is incredibly effective at inhibiting such necrosis caused by African spitting cobras; an exciting finding as their venoms are particularly fast-acting and destructive. We hope this work helps pave the way to future snakebite therapies that can save the lives and limbs of victims worldwide." Professor Casewell's team are already looking for viable treatments that effectively block the venom CTx. Having treatments available against both toxins has the potential to enhance the potency of varespladib, and could significantly reduce the long-term morbidity associated with spitting cobra bites in Africa and beyond.

Scientists discovered antibodies that protect against a host of lethal snake venoms. Scripps Research scientists have developed an antibody that can block the effects of lethal toxins in the venoms of a wide variety of snakes found throughout Africa, Asia and Australia. The antibody, which protected mice from the normally deadly venom of snakes including black mambas and king cobras, is described on February 21, 2024, in Science Translational Medicine. The new research used forms of the toxins produced in the laboratory to screen billions of different human antibodies and identify one that can block the toxins' activity. It represents a large step toward a universal antivenom that would be effective against the venom of all snakes. "This antibody works against one of the major toxins found across numerous snake species that contribute to tens of thousands of deaths every year," says senior author Joseph Jardine, PhD, assistant professor of immunology and microbiology at Scripps Research. "This could be incredibly valuable for people in low- and middle-income countries that have the largest burden of deaths and injuries from snakebites." More than 100,000 people a year, mostly in Asia and Africa, die from snakebite envenoming -- rendering it more deadly than most neglected tropical diseases. Current antivenoms are produced by immunizing animals with snake venom, and each generally only works against a single snake species. This means that many different antivenoms must be manufactured to treat snake bites in the different regions. Jardine and his colleagues have previously studied how broadly neutralizing antibodies against the human immunodeficiency virus (HIV) can work by targeting areas of the virus that cannot mutate. They realized that the challenge of finding a universal antivenom was similar to their quest for an HIV vaccine; just like quickly evolving HIV proteins show small differences between each other, different snake venoms have enough variations that an antibody binding to one generally doesn't bind to others. But like HIV, snake toxins also have conserved regions that cannot mutate, and an antibody targeting those could possibly work against all variants of that toxin. In the new work, the researchers isolated and compared venom proteins from a variety of elapids -- a major group of venomous snakes including mambas, cobras and kraits. They found that a type of protein called three-finger toxins (3FTx), present in all elapid snakes, contained small sections that looked similar across different species. In addition, 3FTx proteins are considered highly toxic and are responsible for whole-body paralysis, making them an ideal therapeutic target. With the goal of discovering an antibody to block 3FTx, the researchers created an innovative platform that put the genes for 16 different 3FTx into mammalian cells, which then produced the toxins in the lab. The team then turned to a library of more than fifty billion different human antibodies and tested which ones bound to the 3FTx protein from the many-banded krait (also known as the Chinese krait or Taiwanese krait), which had the most similarities with other 3FTx proteins. That narrowed their search down to about 3,800 antibodies. Then, they tested those antibodies to see which also recognized four other 3FTx variants. Among the 30 antibodies identified in that screen, one stood out as having the strongest interactions across all the toxin variants: an antibody called 95Mat5. "We were able to zoom in on the very small percentage of antibodies that were cross-reactive for all these different toxins," says Irene Khalek, a Scripps Research scientist and first author of the new paper. 'This was only possible because of the platform we developed to screen our antibody library against multiple toxins in parallel." Jardine, Khalek and their colleagues tested the effect of 95Mat5 on mice injected with toxins from the many-banded krait, Indian spitting cobra, black mamba and king cobra. In all cases, mice who simultaneously received an injection of 95Mat5 were not only protected from death, but also paralysis. When the researchers studied exactly how 95Mat5 was so effective at blocking the 3FTx variants, they discovered that the antibody mimicked the structure of the human protein that 3FTx usually binds to. Interestingly, the broad-acting HIV antibodies that Jardine has previously studied also work by mimicking a human protein. "It's incredible that for two completely different problems, the human immune system has converged on a very similar solution," says Jardine. "It also was exciting to see that we could make an effective antibody entirely synthetically -- we did not immunize any animals nor did we use any snakes." While 95Mat5 is effective against the venom of all elapids, it does not block the venom of vipers -- the second group of venomous snakes. Jardine's group is now pursuing broadly neutralizing antibodies against another elapid toxin, as well as two viper toxins. They suspect that combining 95Mat5 with these other antibodies could provide broad coverage against many -- or all -- snake venoms. "We think that a cocktail of these four antibodies could potentially work as a universal antivenom against any medically relevant snake in the world," says Khalek. This work was supported by funding from the National Institutes of Health (R35 CA231991, U01 AI142756, RM1 HG009490, R35 GM118062, R35 GM118069), the Damon Runyon Cancer Research Foundation (2406-20), the Jane Coffin Childs Fund, the Mark Foundation for Cancer Research and the Howard Hughes Medical Institute.