Varespladib for Snake Bites

(BRAVIO Trial)

Recruiting at 10 trial locations

Overseen By Brandi Ritter PA-C, MPAS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ophirex, Inc.

Must not be taking: Anticoagulants, Antiarrhythmics

Disqualifiers: CVA, Intracranial bleeding, Liver disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

140 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a multicenter,randomized,double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability and efficacy of a continuous rate infusion (CRI) of IV varespladib followed by transition to the oral dosage form, varespladib-methyl, concurrently with SOC, in participants bitten by venomous snakes. Note: Funding Source - FDA-OOPD

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking all current medications. However, you cannot participate if you are using certain anticoagulants or antiarrhythmic drugs within 14 days before treatment.

What data supports the idea that Varespladib for Snake Bites is an effective drug?

The available research shows that Varespladib is effective in treating snake bites by inhibiting a key venom component called phospholipase A2 (PLA2). In one study, 80% of mice treated with Varespladib and venom survived, while all mice given venom alone died. Another study found that Varespladib significantly reduced muscle damage and other toxic effects in animal models. These results suggest that Varespladib could be a promising alternative or addition to traditional antivenom treatments. ^{1 2 3 4 5}

What safety data exists for Varespladib as a treatment?

Varespladib has been evaluated in 29 clinical studies involving over 4600 human subjects for non-snakebite conditions, where it was generally well-tolerated and considered safe. It is currently in Phase 2 clinical trials for snakebite treatment. Preclinical studies and animal models have shown promising results in inhibiting snake venom toxicity. ^{1 2 3 4 5}

Is the drug Varespladib a promising treatment for snake bites?

Yes, Varespladib is a promising drug for treating snake bites. It works by blocking a key component in snake venom called phospholipase A2 (PLA2), which is responsible for many of the harmful effects of the venom. Studies have shown that Varespladib can effectively reduce the toxic effects of snake venom, improve survival rates in animal models, and potentially serve as a first-line treatment for snakebite envenomation. ^{1 2 3 4 6}

Research Team

Timothy Platts-Mills, MD, MSc

Principal Investigator

Ophirex, Inc.

Eligibility Criteria

Adults (18+) with a venomous snakebite within the last 10 hours can join this trial. They must have certain symptoms measured by an inclusion score and agree to informed consent. People with severe heart, bleeding, or liver conditions, kidney disease, allergies to varespladib, on certain anticoagulants or antiarrhythmics recently, pregnant or breastfeeding women cannot participate.

Inclusion Criteria

I was bitten by a Russell's viper or krait in India.

This criterion does not apply to me.

In the U.S., any snakebite that meets all other criteria may be eligible

Exclusion Criteria

I have a history of chronic liver disease.

Known allergy or significant adverse reaction to varespladib or varespladib-methyl

Considered by the Investigator to be unable to comply with protocol requirements due to geographic considerations, psychiatric disorders, or other compliance concerns

Treatment Details

Interventions

• Varespladib

Trial Overview The BRAVIO study is testing IV varespladib followed by oral varespladib-methyl against placebos in addition to standard care for snakebites. It's a phase 2 trial where participants are randomly assigned treatments in a double-blind manner so neither they nor the researchers know who gets what.

Participant Groups

Group I: Varespladib Intravenous Form (IV) + Varespladib Oral tablet (LY315920) + SOC Experimental Treatment 2 Interventions

Participants will receive intravenous (IV) infusion of varespladib at dose of 0.45 milligrams per kilogram per hour (mg/kg/hr) for six hours. This infusion will continue until when the participant meets clinical criteria for transition to oral drug, -If criteria are met, they will be transitioned to varespladib-methyl (initial dose of 500 mg) then continued oral dosing q12 (once every 12 hours) of 250 mg for the remainder of the study period. Participants that do not meet the criteria for transitioning to the oral drug will remain on the IV infusion at 0.45 mg/kg/hr (along with SOC) and assessed twice a day until they meet criteria for transition to oral drug.

Group II: Placebo Intravenous (IV) + Placebo Oral + SOC Active Control 2 Interventions

Participants will receive intravenous (IV) infusion of placebo matched to varespladib for six hours. This infusion will continue until the participant meets clinical criteria for transition to oral drug. If criteria are met, they will be transitioned to the oral placebo then continued oral dosing for the remainder of the study period. Participants that do not meet the criteria for transitioning to the oral drug will remain on the IV infusion (along with SOC) and assessed twice a day until they meet criteria for transition to oral drug.

Varespladib is already approved in United States, India for the following indications:

Approved in United States as Varespladib for:

• Snakebite envenoming

Approved in India as Varespladib for:

• Snakebite envenoming

Who Is Running the Clinical Trial?

Ophirex, Inc.

Lead Sponsor

Trials

3

Recruited

250+

Findings from Research

Varespladib effectively inhibits the toxic effects of snake venom phospholipase A₂, showing significant protective effects against hemorrhage and muscle damage in animal models of envenomation.

In studies with mice, varespladib treatment significantly reduced muscle edema and biochemical markers of organ injury, suggesting it could be a promising first-line treatment for snakebite envenomation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation. Wang, Y., Zhang, J., Zhang, D., et al.[2022]

Varespladib has been shown to effectively inhibit the myotoxic and cytotoxic effects of the snake venom component MjTX-I, suggesting its potential as a complementary treatment alongside traditional antivenoms.

The study utilized advanced techniques like X-ray crystallography and mass spectroscopy to reveal the unique inhibitory mechanism of varespladib, indicating it may serve as a multifunctional inhibitor for various PLA2 and PLA2-like toxins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The synthetic varespladib molecule is a multi-functional inhibitor for PLA2 and PLA2-like ophidic toxins. Salvador, GHM., Borges, RJ., Lomonte, B., et al.[2021]

The BRAVO study is a phase 2 clinical trial designed to evaluate the safety and efficacy of varespladib-methyl, an oral treatment for snakebite envenoming, involving patients aged 5 and older from various geographic locations.

The primary outcome of the study is the modified Snakebite Severity Score, which assesses the impact of snake venom on multiple body systems, indicating a comprehensive approach to evaluating the treatment's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The BRAVO Clinical Study Protocol: Oral Varespladib for Inhibition of Secretory Phospholipase A2 in the Treatment of Snakebite Envenoming. Carter, RW., Gerardo, CJ., Samuel, SP., et al.[2023]

Varespladib, an inhibitor of snake phospholipase, shows promise as a first-line therapy against the toxic effects of Nikolsky's viper venom, significantly improving survival rates in a mouse model.

In the study, 80% of mice treated with Varespladib and venom survived, compared to 100% mortality in the control group receiving only venom, indicating Varespladib's potential as an effective antitoxin against this specific snake venom.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PLA2 Inhibitor Varespladib as an Alternative to the Antivenom Treatment for Bites from Nikolsky's Viper Vipera berus nikolskii. Zinenko, O., Tovstukha, I., Korniyenko, Y.[2021]

Varespladib, a synthetic inhibitor of venom toxins, shows promise as a treatment for snakebite envenoming, potentially improving outcomes when used alongside traditional antivenom.

With over 29 clinical studies involving more than 4600 participants demonstrating its safety and tolerability for other conditions, varespladib is now advancing to Phase 2 clinical trials specifically for snakebite treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Varespladib in the Treatment of Snakebite Envenoming: Development History and Preclinical Evidence Supporting Advancement to Clinical Trials in Patients Bitten by Venomous Snakes. Lewin, MR., Carter, RW., Matteo, IA., et al.[2023]

Varespladib and its prodrug methyl-Varespladib effectively inhibit the neurotoxic effects of certain snake venoms in a mouse model, with some mice surviving longer than those receiving venom alone.

LY315920 was particularly effective in reversing paralysis caused by specific venoms, indicating its potential as a treatment for snakebite envenomation, although further research is needed to explore its clinical applications in humans and animals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Varespladib (LY315920) and Methyl Varespladib (LY333013) Abrogate or Delay Lethality Induced by Presynaptically Acting Neurotoxic Snake Venoms. Gutiérrez, JM., Lewin, MR., Williams, DJ., et al.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

The synthetic varespladib molecule is a multi-functional inhibitor for PLA2 and PLA2-like ophidic toxins. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

The BRAVO Clinical Study Protocol: Oral Varespladib for Inhibition of Secretory Phospholipase A2 in the Treatment of Snakebite Envenoming. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

PLA2 Inhibitor Varespladib as an Alternative to the Antivenom Treatment for Bites from Nikolsky's Viper Vipera berus nikolskii. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Varespladib in the Treatment of Snakebite Envenoming: Development History and Preclinical Evidence Supporting Advancement to Clinical Trials in Patients Bitten by Venomous Snakes. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Varespladib (LY315920) and Methyl Varespladib (LY333013) Abrogate or Delay Lethality Induced by Presynaptically Acting Neurotoxic Snake Venoms. [2021]