Working to revolutionize
snakebite treatment
Ophirex is in advanced development of varespladib as a first-of-its-kind oral rescue treatment for snakebite. Varespladib is a potent small-molecule inhibitor of snake venom secretory phospholipase A2 (sPLA2), a class of toxins present in the venom of more than 95% of snake species that contributes to lethality.1,2 Among U.S. vipers, all highly toxic venoms contain sPLA2 neurotoxins.3
In 2022, varespladib received FDA Fast Track designation, recognizing its potential to address the significant unmet need for treating snakebite.
Foundational research on
varespladib
Evolving how we study
snakebite in humans
The study of efficacy for any novel therapy in snakebite is complex, because the occurrence of snakebite is unpredictable and typically occurs in suburban and rural areas and because it is unethical to withhold the standard of care of antivenom. As a result, administration of varespladib in clinical trials typically occurs several hours after the administration of antivenom. This differs from the urgent need that varespladib is intended to address: to provide a rescue treatment to be used when antivenom is not immediately available.
The FDA Animal Rule anticipates this type of challenge by permitting approval of drugs for human use based on well-controlled animal studies, when human efficacy trials are unethical or infeasible. Ophirex is pursuing the Animal Rule regulatory pathway for varespladib for the treatment of snakebite.
Upcoming studies of varespladib include well-controlled animal studies that will establish the benefit from varespaldib for a broad range of venoms and human studies to establish the safety of a fully effective dose.
Clinical studies
of varespladib
Two clinical trials have been conducted to further understand the efficacy and safety of varespladib as an in-hospital treatment in addition to antivenom.
The Phase 2 randomized, placebo-controlled BRAVO trial of oral varespladib for snakebite envenomation enrolled 95 patients in emergency rooms in the United States and India.10 Varespladib was well-tolerated. While the trial did not meet its primary endpoints, there were positive signals in multiple secondary and exploratory endpoints in the prespecified subgroup of patients initiating study drug within five hours of bite.
The Phase 2 randomized, placebo-controlled BRAVIO trial of intravenous followed by oral varespladib for snakebite envenomation enrolled 139 patients in emergency rooms in the United States and India. Results from the trial have been submitted for publication
Both the BRAVO and BRAVIO trials tested varespladib in patients who had already received antivenom, with the average time from bite to treatment with study drug exceeding 6 hours in BRAVO and exceeding 7 hours in BRAVIO. The trial design reflects the logistical constraints of hospital-based trials for a rare disease. These studies do not test varespladib in the manner of its intended use if approved: as an early field treatment or as the initial treatment in the emergency room.
No serious adverse events were observed in varespladib-treated patients in either BRAVO or BRAVIO. Additionally, prior studies of varespladib conducted by earlier sponsors for a range of conditions based on treatment in more than 4,000 people provide a well-characterized safety profile. Ophirex is using these studies as part of a comprehensive safety database to establish the safety of varspladib at dose levels effective for treating snakebite.
Partnering to support snakebite
treatment innovation
Publications
Expanded Access Policy
Citations
- Lewin M, Samuel S, Merkel J, Bickler P. Varespladib (LY315920) appears to be a potent, broad-spectrum inhibitor of snake venom phospholipase A₂ and a possible pre-referral treatment for envenomation. Toxins (Basel). 2016;8(9):248. doi:10.3390/toxins8090248
- Lewin MR, Carter RW, Matteo IA, et al. Varespladib in the treatment of snakebite envenoming: development history and preclinical evidence supporting advancement to clinical trials in patients bitten by venomous snakes. Toxins (Basel). 2022;14(11):783. doi:10.3390/toxins14110783
- Mackessy SP. Venom composition in rattlesnakes: trends and biological significance. In: Hayes WK, Beaman KR, Cardwell MD, Bush SP, eds. The Biology of Rattlesnakes. Loma Linda, CA: Loma Linda University Press; 2008:495-510.
- Wang Y, Zhang J, Zhang D, Xiao H, Xiong S, Huang C. Exploration of the inhibitory potential of varespladib for snakebite envenomation. Molecules. 2018;23(2):391. doi:10.3390/molecules23020391
- Tan CH, Lingam TMC, Tan KY. Varespladib (LY315920) rescued mice from fatal neurotoxicity caused by venoms of five major Asiatic kraits (Bungarus spp.) in an experimental envenoming and rescue model. Acta Trop. 2022;227:106289. doi:10.1016/j.actatropica.2021.106289
- Zinenko O, Tovstukha I, Korniyenko Y. PLA₂ inhibitor varespladib as an alternative to the antivenom treatment for
bites from Nikolsky's viper Vipera berus nikolskii. Toxins (Basel). 2020;12(6):356. doi:10.3390/toxins12060356 - Gutiérrez JM, Lewin MR, Williams DJ, Lomonte B. Varespladib (LY315920) and methyl varespladib (LY333013) abrogate
or delay lethality induced by presynaptically acting neurotoxic snake venoms. Toxins (Basel). 2020;12(2):131.
doi:10.3390/toxins12020131 - Xie C, Albulescu LO, Still KB, et al. Varespladib inhibits the phospholipase A2 and coagulopathic activities of venom
components from hemotoxic snakes. Biomedicines. 2020;8(6):165. doi:10.3390/biomedicines8060165 - Bartlett KE, Hall SR, Rasmussen SA, et al. Dermonecrosis caused by a spitting cobra snakebite results from toxin
potentiation and is prevented by the repurposed drug varespladib. Proc Natl Acad Sci U S A.
2024;121(19):e2315597121. doi:10.1073/pnas.2315597121 - Gerardo CJ, Carter RW, Kumar S, et al. Oral varespladib for the treatment of snakebite envenoming in India and the
USA (BRAVO): a phase II randomized clinical trial. BMJ Glob Health. 2024;9(10):e015985. doi:10.1136/bmjgh-2024-
015985