Varespladib for Snake Bites

(BRAVIO Trial)

No longer 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

Duration: 14 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a potential new treatment, varespladib, for individuals bitten by venomous snakes. Researchers aim to determine if varespladib, administered first through an IV and then as a pill, is safe and effective alongside standard care. The trial compares this treatment to a placebo to assess its true impact. Suitable participants include adults bitten by a venomous snake, especially within a few hours, who are experiencing specific symptoms. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that varespladib is safe and well-tolerated for treating snakebite poisoning. Studies, including the BRAVO trial, have provided extensive safety data supporting its use. Participants in these studies generally responded well to the treatment, with no major safety issues reported.

Researchers have tested varespladib both as an IV infusion and in pill form. Data from these studies suggest that people taking varespladib experience few side effects, supporting its potential as a safe option for those affected by snakebites.

Overall, existing research provides reassuring evidence about the safety of varespladib for those considering joining a clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard of care for snake bites, which typically involves antivenom administration, Varespladib offers a novel approach by directly inhibiting secretory phospholipase A2 (sPLA2) enzymes, which are key contributors to venom toxicity. This mechanism of action is different because it targets the enzymes responsible for venom-induced damage, potentially reducing symptoms and complications more effectively. Researchers are excited about Varespladib because it not only provides a new way to neutralize snake venom but also has the potential to be administered both intravenously and orally, offering flexibility in treatment and possibly improving patient outcomes.

What evidence suggests that varespladib might be an effective treatment for snake bites?

Research shows that varespladib might help treat snake bites. Studies have found that it can lessen the effects of snake venom and may prevent serious symptoms. The medication works by blocking certain harmful enzymes in the venom. In this trial, participants will receive either varespladib or a placebo, both alongside standard of care (SOC). Early results from other trials indicate that patients at risk of severe problems from snake bites recovered better when treated with varespladib. These findings are encouraging for those seeking effective treatments for venomous snake bites. ^{1 2 4 6 7}

Who Is on the Research Team?

Timothy Platts-Mills, MD, MSc

Principal Investigator

Ophirex, Inc.

Are You a Good Fit for This Trial?

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.

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

Is willing (or legally authorized representative is willing) to provide informed consent prior to initiation of any study procedures

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive intravenous infusion of varespladib or placebo followed by transition to oral dosing

14 days

Daily assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

14 days

Extended Follow-up

Complete recovery assessment using the Snakebite Severity Scale Score

28 days

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9695340/

Varespladib in the Treatment of Snakebite Envenoming Additionally, data suggest that snakebite envenoming is disproportionately severe in childhood with worse outcomes ... efficacy of varespladib ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0041010125004015

In vitro inhibition of snake venom toxins by varespladib, ... These data demonstrate that SMTs are effective inhibitors of the relevant enzymes in several snake species and support the proposal that ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32093386/

Varespladib (LY315920) and Methyl ... Overall, results suggest that the two forms of Varespladib are effective in abrogating, or delaying, neurotoxic manifestations induced by ...

4. ophirex.com ophirex.com/20241023-ophirex-publishes-phase-2-data-in-bmj-global-health

Ophirex Publishes Varespladib Phase 2 Data in BMJ ... Results from the BRAVO trial also suggest that varespladib ... outcomes for patients at risk of death and long-term disability from snakebite.

5. gh.bmj.com gh.bmj.com/content/9/10/e015985

Oral varespladib for the treatment of snakebite envenoming ... The primary outcome was change in the composite Snakebite Severity Score (SSS) measuring the severity of envenoming, from baseline to the average composite SSS ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04996264

Broad-spectrum Rapid Antidote: Varespladib Oral for ... This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability and efficacy of varespladib- ...

7. ycmd.yale.edu ycmd.yale.edu/sites/default/files/files/Toxins_Varespladib_Lewin%20et%20al_2016.pdf

Varespladib (LY315920) Appears to Be a Potent, Broad ... Nevertheless, our results suggest varespladib-based therapies could be plausible first-line treatments for a diversity of snakebites alone or in ...