Ophirex Publishes Phase 2 BRAVIO Data: Varespladib Misses Primary Endpoints but Shows Benefit Signals in Krait and Copperhead Bites
核心洞察
Ophirex (搜索) published Phase 2 BRAVIO results in PLOS Neglected Tropical Diseases, evaluating intravenous then oral varespladib added to antivenom in 140 hospitalized snakebite patients.
The trial did not meet its prespecified primary endpoints for elapid and viper envenoming, with varespladib started a mean 7.3 hours after the bite.
Varespladib-treated krait patients spent roughly half as long on mechanical ventilation, 21 versus 40 hours, and had 36% lower illness severity over the first week.
Ophirex (搜索) has published results from the Phase 2 BRAVIO trial of varespladib in patients with snakebite envenomation (搜索) in PLOS Neglected Tropical Diseases. The multicenter, randomized, double-blind, placebo-controlled study evaluated intravenous sodium varespladib followed by oral methyl varespladib, added to standard antivenom therapy, in 140 hospitalized patients (139 analyzed) across 18 sites in India and the United States. Patients were assigned 1:1 to varespladib or placebo in addition to antivenom.
The trial did not meet its prespecified primary endpoints: time to recovery of 5-second head-lift for elapid envenoming, and area under the curve (AUC) from baseline to Day 14 of a 3-item Snakebite Severity Score (SSS) comprising the local wound, hematologic and neurologic subscores for viper envenoming. On average, varespladib was initiated 7.3 hours after the snakebite and 3.3 hours after antivenom.
Signals of Benefit in sPLA2-Driven Envenoming
Varespladib did show a signal of benefit in patients bitten by snakes with well-defined sPLA2-driven toxicities, including elapids and copperheads. Among elapid patients, primarily those bitten by kraits, varespladib-treated patients (n=24) spent approximately half as much time on mechanical ventilation, 21 hours versus 40 hours, and experienced 36% lower illness severity over the first week. Copperhead patients treated with varespladib (n=12) experienced a 43% reduction in illness severity over the first two weeks.
"The study drug was initiated an average of seven hours after snakebite and following the administration of antivenom, making it difficult to measure the true effect of sPLA2 inhibition," said Charles J. Gerardo, MD, co-lead author and Professor at Duke University Hospital. "Giving antivenom up front was necessary due to the severity of snakebite envenomation (搜索) within the trial. Nonetheless, varespladib, as a late adjunctive therapy, was associated with clinically meaningful signals of benefit in krait and copperhead patients. These results are consistent with the known mechanism of action of varespladib and point to the need for further studies."
Varespladib was well tolerated across the study population, and no serious adverse events were reported in varespladib-treated patients. Enrolled patients were bitten by a range of elapids and vipers, including kraits, Russell's vipers, rattlesnakes and copperheads, with sites selected to provide broad geographic representation and capture a diverse range of medically important snake species.
Mechanism and Regulatory Path
Varespladib is a small-molecule inhibitor of snake venom secretory phospholipase A2 (搜索) (sPLA2), a major snake venom toxin present in at least 95% of venomous snake species worldwide with multiple effects, including neurotoxicity, local tissue injury and hemorrhage. The compound is being studied as a broad-spectrum snakebite treatment that binds to and inactivates sPLA2 regardless of the snake species, neutralizing its activity and mitigating downstream toxic effects.
"The results in krait- and copperhead-bite patients are aligned with the benefits observed in animal experiments," said Timothy Platts-Mills, M.D., MSc, Chief Medical Officer of Ophirex (搜索). "To study the effects of varespladib in humans in a use case more similar to its intended use, as an oral rescue treatment administered at the time of bite, before antivenom, Ophirex is continuing the study of varespladib via the FDA's Animal Rule, under which efficacy data from adequate and well-controlled animal studies form the basis for approval. This is the appropriate regulatory pathway in instances when human efficacy trials are unethical or infeasible. If approved, we anticipate additional post-approval clinical studies will evaluate the effects of prehospital and early in-hospital treatment."
Varespladib has received FDA Orphan Drug, Pediatric Rare Disease and Fast Track designations. It is being developed with support from the Defense Health Agency's Small Business Innovation Research (DHA SBIR) program and the Warfighter Protection and Acute Care (WPAC) team under the Broad-Spectrum Snakebite Antidote (BSSA) program. The FDA's Center for Veterinary Medicine has granted Minor Use in Major Species (MUMS) designation for the treatment of snakebite in dogs when antivenom is not immediately available.
Unmet Need in Snakebite Envenomation
Snakebite envenomation (搜索) globally results in 80,000 to 138,000 deaths and 400,000 cases of permanent disability each year, primarily in low- and middle-income countries, with more than 50,000 deaths per year in India alone. The majority of deaths occur before patients reach a hospital. Antivenom remains the only pharmacologic treatment available and requires intravenous administration in a medical setting, and delays in its administration are a major contributor to poor outcomes following snakebite.
"There is a significant unmet need for a snakebite treatment that can be administered at the time of bite to immediately inhibit the effects of snake venom," said Jeremy Gowler, CEO of Ophirex (搜索). "We are committed to continuing varespladib's development, and efficacy studies in animals are underway."
The company plans to publish subgroup analyses of varespladib administration in patients bitten by krait and copperhead snakes in the next few months.