Broad-spectrum Rapid Antidote: Varespladib Oral for Snakebite (BRAVO)

Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of a Multi-Dose Regimen of Oral Varespladib-Methyl in Subjects Bitten by Venomous Snakes

This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability and efficacy of varespladib-methyl, concurrently with standard of care (SOC), in subjects bitten by venomous snakes.

Study Overview

• Status: Completed
• Conditions: Snakebites; Envenoming; Envenoming, Snake; Envenomation, Snake
• Intervention / Treatment: Drug: Varespladib Methyl; Drug: Standard of care (SOC); Drug: Placebo

Detailed Description

This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability, and efficacy of varespladib-methyl, concurrently with SOC, in subjects bitten by venomous snakes.

Approximately 110 male and female eligible subjects will be enrolled and randomized to receive active varespladib-methyl or placebo (in addition to SOC) in a 1:1 ratio (approximately 36 per group). There will be no stratification by type of snakebite, though randomization will be stratified by age group (5 to 11 years, 12 to 17 years, and ≥ 18 years) and by the presence or absence of severe neurologic symptoms defined by yes/no neurologic system subscore of the snakebite severity score of ≥ 2.

Effective treatments for snakebite envenoming represents a deadly and unmet global medical need. While antivenoms comprise the SOC for treatment of snakebites, they suffer from several limitations including specificity of each antivenom for specific species of snake, limited access to antivenom in rural areas, practical storage requirements, and delays in administration. Treatment of snakebite envenoming with the small-molecule drug varespladib-methyl, which targets secreted phospholipase A₂ (sPLA₂) present in more than 95% of snake venoms, has the potential to overcome several limitations of serum-based antivenoms that underpin traditional SOC.

This study in the United States and India will provide coverage of a broad spectrum of venomous snake genera, including elapids, pit vipers, and potentially exotics such as vipers and colubrids if encountered over the course of the study. The study is designed to cover differing geographies and differing sPLA₂ structures. Study sites have been and will be selected based on demonstrated historical incidence of snake bites from species deemed relevant to this study, to ensure a broad range of envenoming toxins are expected to be encountered in potential study subjects.

The study design allows for both treatment arms (varespladib-methyl and placebo) to receive SOC (e.g., antivenom) concurrently. Thus, critically ill adult and pediatric subjects may receive emergency treatment in a timely manner while being evaluated for the potential clinical benefit associated with inhibition of venom sPLA₂ and inflammatory sPLA2s by varespladib-methyl.

Because subjects with severe snakebites are admitted to emergency departments, this study was designed to screen, enroll, and administer treatment in a single visit at the hospital upon admission. Because varespladib-methyl is administered orally, subjects who demonstrate substantial improvement and are eligible for discharge from the hospital may continue investigational product treatment in an outpatient setting.

Risks associated with the control (placebo) arm of this study include the same risks associated with SOC (antivenom).

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Brandi Ritter, MPAS; Phone Number: 5302184454; Email: brandi@ophirex.com

Study Locations

• India
  • Chandigarh, India
    • Postgraduate Institute of Medical Education and Research
  • Calicut
    • Kozhikode, Calicut, India
      • Government Medical College
  • Karnataka
    • Mangalore, Karnataka, India, 575002
      • Father Muller Medical College Hospital
    • Mysore, Karnataka, India
      • K R Hospital Mysore medical College and Research Institute
  • Kerala
    • Thrissur, Kerala, India
      • Jubilee Mission Medical College and Research Institute
  • Puducherry
    • Pondicherry, Puducherry, India
      • Jawaharlal Institute of Postgraduate Medical Education & Research
  • Rajasthan
    • Bikaner, Rajasthan, India
      • S.P. Medical College Snakebite Research Cell
  • West Bengal
    • Kolkata, West Bengal, India
      • Calcutta National Medical College
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Agusta University Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Chandler Medical Center
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • LSU LA Poison Control Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center - Jackson
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Hospital Durham, NC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Is a male or female subject ≥ 5 years of age with venomous snakebite and must present with an initial SSS of

   • 2 points in any SSS category other than gastrointestinal and 1 or more additional points in any other SSS category other than gastrointestinal or
   • ≥ 3 in any SSS category other than gastrointestinal.

   SSS scoring should be performed for inclusion assessment without waiting for receipt of Baseline hematological laboratory results. Gastrointestinal scores should not be used for inclusion.

2. Index event (snakebite) must be symptomatic and must have occurred within 10 hours of eligibility assessment.

3. Must meet one of two categories of inclusion criteria:

   Category 1: The patient has not yet completed first dose of antivenom:

   SSS inclusion score* of ≥2 in one system and ≥1 in another system (2+1) OR ≥3 in at least one system.

   OR

   Category 2: The patient has completed an initial dose of antivenom:

   SSS inclusion score* of ≥2 in one system and ≥1 in another system (2+1) OR ≥3 in at least one system AND CGI-I score of ≥5 (i.e., minimally worse, much worse, or very much worse).

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

Exclusion Criteria:

1. Has received antivenom treatment for envenoming prior to enrollment in this study.
2. Is considered by the investigator to have a clinically significant upper GI bleed evidenced by hematemesis, "coffee-ground" emesis or nasogastric aspirate, or hematochezia thought to originate from upper GI tract.
3. Has history of cerebrovascular accident or intracranial bleeding of any kind, acute coronary syndrome, myocardial infarction, or severe pulmonary hypertension.
4. Has known history of inherited bleeding or coagulation disorder.
5. Is, at Screening Visit, using the following anticoagulants: warfarin/coumadin, argatroban, bivalirudin, lepirudin, apixaban, dabigatran, clopidogrel, prasugrel, ticlopidine or another anticoagulant agent not specifically listed, or has used heparin, enoxaparin, fondaparinux, or other low molecular weight heparin or antiarrhythmic drugs within 14 days prior to treatment.
6. Has a history of chronic liver disease such as chronic active viral hepatitis, alcohol-related liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, or autoimmune hepatitis.
7. Reports or has known pre-existing renal impairment or chronic kidney disease (defined as Stage 4 or receiving dialysis or hemofiltration).
8. Has a known allergy or significant adverse reaction to varespladib-methyl or related compounds.
9. Is considered by the Investigator to be unable to comply with protocol requirements due to geographic considerations, psychiatric disorders, or other compliance concerns.
10. Is pregnant, has a positive serum human chorionic gonadotropin (hCG) pregnancy test or not willing to use a highly effective method of contraception for 14 days after initial treatment, or is breast-feeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Varespladib-methyl; Varespladib-methyl is an immediate-release (IR), oval, white, film-coated tablet at a dosage strength of 250 mg for oral administration. Scaled pediatric doses of varespladib-methyl are supplied as 50 mg IR capsules for oral administration. Adult subjects will receive an initial loading dose of 500 mg (2 × 250 mg oral tablet) varespladib-methyl upon randomization, followed by dosing with 250 mg varespladib-methyl (1 × 250 mg oral tablet) approximately 12 hours later, and subsequent twice daily (BID) dosing with 1 × 250 mg varespladib-methyl oral tablets for the remainder of the 7-day treatment period. Tablets may be administered via naso- or orogastric tubes in patients requiring mechanical ventilation. Pediatric subjects (5 to < 18 years) will be administered doses of varespladib-methyl determined by allometric scaling, provided as 50 mg capsules. Age-appropriate capsules may be administered via naso- or orogastric tubes in patients requiring mechanical ventilation.	Drug: Varespladib Methyl; Varespladib-methyl (LY333013) is an IR, oval, white, film-coated tablet at a dosage strength of 250 mg for oral administration. Scaled pediatric doses of varespladib-methyl (LY333013) are supplied as 50 mg IR capsules for oral administration.; Other Names: LY333013; Drug: Standard of care (SOC); SOC (including antivenom) will continue to be administered throughout the subject's participation in the study according to the protocol and the judgment of the Investigator.
Placebo Comparator: Placebo; The oral placebo is supplied as a white film-coated oval tablet to match the appearance of the varespladib-methyl 250 mg tablet and contains a subset of the excipients present in the active tablet formulation: lactose monohydrate, microcrystalline cellulose, and magnesium stearate. Placebo for scaled pediatric dosing is supplied as an immediate-release capsule to match the varespladib-methyl 50 mg capsule, and contains the excipients lactose monohydrate, microcrystalline cellulose, and magnesium stearate. The dosing of placebo will match that of varespladib-methyl.	Drug: Standard of care (SOC); SOC (including antivenom) will continue to be administered throughout the subject's participation in the study according to the protocol and the judgment of the Investigator.; Drug: Placebo; The oral placebo is supplied as a white film-coated oval tablet to match the appearance of the varespladib-methyl 250 mg tablet and contains a subset of the excipients present in the active tablet formulation: lactose monohydrate, microcrystalline cellulose, and magnesium stearate. Placebo for scaled pediatric dosing is supplied as an IR capsule to match the varespladib-methyl 50 mg capsule, and contains the excipients lactose monohydrate, microcrystalline cellulose, and magnesium stearate.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the combined pulmonary, cardiovascular, hematologic, and nervous system subscores of the snakebite severity score (SSS)	Change from baseline (pre-dosing) to 6 and 9 hours after the first dose, in the combined pulmonary, cardiovascular, hematologic symptoms, and nervous system subscores of the SSS. The values from each of these 4 subscores will be totaled. The average of the 6- and 9-hour scores will be used as the post-treatment value. The SSS is a tool used to measure the severity of envenoming based on 6 body categories: local wound, pulmonary, cardiovascular, gastrointestinal (graded at levels from Grade 0 to Grade 3), hematological, and nervous system effects (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms.	Baseline to 6 and 9 hours after first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the curve (AUC) of the pulmonary, cardiovascular, hematologic symptoms, renal, and nervous system sections of the SSS	Absolute values and change from baseline (pre-dosing) through Day 7 in the AUC of the pulmonary, cardiovascular, hematologic symptoms, and nervous system sections of the SSS. The SSS is a tool used to measure the severity of envenoming based on 6 body categories: local wound, pulmonary, cardiovascular, gastrointestinal (graded at levels from Grade 0 to Grade 3), hematological, and nervous system effects (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms.	Baseline through Day 7
Complete SSS scores	Absolute values and change from baseline (pre-dosing) through Day 7 in the complete SSS. The SSS is a tool used to measure the severity of envenoming based on 6 body categories: local wound, pulmonary, cardiovascular, gastrointestinal (graded at levels from Grade 0 to Grade 3), hematological, and nervous system effects (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms.	Baseline through Day 7
Percent of patients with hematological abnormalities	The percent of patients who had an SSS hematology score ≥ 2 at baseline with coagulation abnormalities from baseline (pre-dosing) through Day 7.	Baseline through Day 7
Hemolysis markers: percent of patients for each visual hemolysis score level and abnormal lactate dehydrogenase (LDH)	The percent of patients for each visual hemolysis score level and abnormal LDH from baseline (pre-dosing) through Day 3.	Baseline through Day 3
Hemolysis markers: quantitative hemolysis score occurrence	The quantitative hemolysis score occurrence (yes/no) and occurrence of abnormal LDH values (yes/no) from baseline (pre-dosing) through Day 3.	Baseline through Day 3
Levels of myonecrosis marker, creatine kinase (CK)	Absolute value and change from baseline in CK from baseline (pre-dosing) through Day 3. Only patients with ≥ 2× institutional reference range at Baseline and gross hemolysis at baseline will be included.	Baseline through Day 3
Total antivenom requirement	Total amount of antivenom given from baseline (pre-dosing) through Day 28.	Baseline through Day 28
Patients requiring ventilatory support	The percent of patients requiring ventilatory support from baseline (pre-dosing) through Day 28.	Baseline through Day 28
Total duration of ventilatory support	Total duration (days) of ventilatory support from baseline (pre-dosing) through Day 28.	Baseline through Day 28
Total duration of Intensive Care Unit (ICU) stay	Total duration (days) of ICU stay from baseline (pre-dosing) through Day 28.	Baseline through Day 28
Total duration of hospitalization	Total duration (days) of hospitalization from baseline (pre-dosing) through Day 28. Only hospitalization from baseline through Day 28 will be included.	Baseline through Day 28
All-cause mortality	The number of patients experiencing the event (death) and the number of patients censored from baseline (pre-dosing) through Day 60. The all-cause mortality will be censored at Day 60.	Baseline through Day 60
Clinical Global Impression - Improvement (CGI-I) and Patient Global Impression of Change (PGIC) responders	The proportion of patients with a score on the CGI-I and PGIC of 1: very much improved, or 2: much improved from baseline (pre-dosing) through Day 7. The CGI-I and PGIC are 7-point scales depicting a clinician's/patient's rating of overall improvement, with scores ranging from 1 (very much improved) to 7 (very much worse).	Baseline through Day 7
Patient-Specific Functional Scale (PSFS) total score	Absolute values and change in the PSFS total score from Day 1 through Day 28. The PSFS is a 3-item instrument which assesses functional abilities. The total score ranges from 0 to 10 with a lower score indicating greater functional difficulties.	Day 1 through Day 28
Numeric Pain Rating Scale (NPRS) score	Absolute values and change from baseline (pre-dosing) through Day 28 in NPRS score in patients able to respond pre-dosing through Day 28. The NPRS is an 11-point scale for patient self-reporting of pain with scores ranging from 0 (no pain) to 10 (worst possible pain).	Baseline through Day 28
Kidney function markers: blood urea nitrogen (BUN) and creatinine	Absolute values and changes from baseline (pre-dosing) through Day 28 in BUN and creatinine levels (mg/dL).	Baseline through Day 28
Snakebite severity score	SSS neurologic system subscore	Baseline through day 3
Area Under the Curve (AUC) of the Numeric Pain Rating Scale (NPRS)	NPRS	From Baseline through Day 3
Clinician Global Impression - Improvement	CGI focus on improvement for Day 2	Day 2

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Snakebite severity score	Absolute values and change from baseline (pre-dosing) through Day 28 in the SSS at 4, 6, and 9 hours, and on Days 2, 3, 7, 14, and 28 after the first dose of varespladib-methyl. The SSS is a tool used to measure the severity of envenoming based on 6 body categories: local wound, pulmonary, cardiovascular, gastrointestinal (graded at levels from Grade 0 to Grade 3), hematological, and nervous system effects (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms.	Baseline through Day 28 after first dose
Grip strength	Absolute values and change from baseline (pre-dosing) through Day 28 in grip strength. The grip strength assessment is an objective measurement of hand function. The patient is asked to grip a dynamometer and squeeze with maximal force. The measurement is repeated for a total of 3 trials and the greatest value is recorded.	Baseline through Day 28
Analgesic use	The proportion of patients reporting any analgesic use from baseline (pre-dosing) through Day 28.	Baseline through Day 28
PGIC scores through Day 28	Absolute values and changes from baseline (pre-dosing) through Day 28 in PGIC scores. The PGIC is a 7-point scale depicting a patient's rating of overall improvement, with scores ranging from 1 (very much improved) to 7 (very much worse).	Baseline through Day 28
Kidney function markers: estimated glomerular filtration rate (eGFR)	Absolute values and changes from baseline (pre-dosing) through Day 28 in eGFR (mL/min).	Baseline through Day 28
Kidney function markers: urinalysis	Number of patients with abnormal urinalysis results from baseline (pre-dosing) through Day 28.	Baseline through Day 28
Complete blood count (CBC)	Percentage of patients with CBC laboratory values below, within, or above the normal range by visit and in relation to baseline.	Baseline through Day 28
Transfusion requirement	The percentage of patients with hemolysis at enrollment with a transfusion event from enrollment through Day 28.	Enrollment through Day 28
C-reactive protein (CRP) levels	Absolute values and changes from baseline (pre-dosing) through Day 14 in CRP.	Baseline through Day 14
D-dimer levels	Number of patients with abnormal D-dimer levels from baseline (pre-dosing) through Day 14.	Baseline through Day 14
Levels of myonecrosis marker (CK)	Absolute values and change from baseline in CK from baseline (pre-dosing) through Day 3 in patients presenting with and without tourniquets at enrollment. Only patients with ≥ 2× institutional reference range at Baseline and gross hemolysis at baseline will be included.	Baseline through Day 3
Secretory phospholipase A₂ (sPLA₂) activity in serum	Absolute value and change from baseline in sPLA₂ activity in serum from baseline (pre-dosing) through Day 7.	Days 1 to 7
Pharmacokinetic (PK) parameters of varespladib-methyl in plasma: area under the curve	Area under the plasma concentration-time curve from time 0 to the time of the last quantifiable plasma concentration (AUC0-t), and area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf). PK samples will be taken from a subset of adult and pediatric patients on Days 1 and 3, and from all patients on Day 7 at the following timepoints: Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 (pre-second dose) hours post-dose; Day 3: pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose; Day 7: pre-dose.	Days 1, 3, and 7
PK parameters of varespladib-methyl in plasma: maximum serum plasma concentration	The rate of absorption using the maximum serum plasma concentration (Cmax). PK samples will be taken from a subset of adult and pediatric patients on Days 1 and 3, and from all patients on Day 7 at the following timepoints: Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 (pre-second dose) hours post-dose; Day 3: pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose; Day 7: pre-dose.	Days 1, 3, and 7
PK parameters of varespladib-methyl in plasma: time of Cmax (Tmax)	Tmax, the time of Cmax. PK samples will be taken from a subset of adult and pediatric patients on Days 1 and 3, and from all patients on Day 7 at the following timepoints: Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 (pre-second dose) hours post-dose; Day 3: pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose; Day 7: pre-dose.	Days 1, 3, and 7
PK parameters of varespladib-methyl in plasma: apparent first order terminal elimination half-life (t1/2)	The apparent first order terminal elimination half-life (t1/2). PK samples will be taken from a subset of adult and pediatric patients on Days 1 and 3, and from all patients on Day 7 at the following timepoints: Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 (pre-second dose) hours post-dose; Day 3: pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose; Day 7: pre-dose.	Days 1, 3, and 7
PK parameters of varespladib-methyl in plasma: apparent terminal phase rate constant (λz)	The apparent terminal phase rate constant (λz). PK samples will be taken from a subset of adult and pediatric patients on Days 1 and 3, and from all patients on Day 7 at the following timepoints: Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 (pre-second dose) hours post-dose; Day 3: pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose; Day 7: pre-dose.	Days 1, 3, and 7
Incidence and severity of adverse events (AEs), serious AEs (SAEs), and AEs leading to discontinuation of Investigational Product (IP)		After obtaining informed consent until 28 days after the last day of study participation
Number of reported treatment-emergent adverse events (TEAEs)		Beginning of treatment until last Follow-Up Visit/Telephone call at Day 28
Rates of reported TEAEs		Beginning of treatment until last Follow-Up Visit at Day 28
Number of patients with a treatment-related SAE	The Investigator will assess each AE's relationship to the IP and categorize as either: Likely related: a reasonable possibility exists of a relationship between the AE and IP. Unlikely related: no reasonable possibility exists of a relationship between the AE and IP.	Beginning of treatment until last Follow-Up Visit/Telephone call at Day 28
Clinical laboratory evaluations	Number of patients with clinically significant abnormal laboratory values for CBC, urinalysis, liver function tests, renal function tests (albumin, creatinine, blood urea nitrogen, and estimated glomerular filtration rate) from baseline (pre-dosing) through Day 28.	Baseline through Day 28
12-lead electrocardiogram (ECG)	The number of patients with normal and abnormal ECGs from baseline (pre-dosing) through Day 28.	Baseline through Day 28
Concomitant medications and analgesics	The number of patients using concomitant medications and analgesics from baseline (pre-dosing) through Day 28.	Baseline through Day 28
Columbia-Suicide Severity Rating Scale (C-SSRS)	Absolute values and change from baseline (pre-dosing) or at the earliest time point clinically allowable (ideally Day 1) and then at every study visit through Day 28. The C-SSRS is a questionnaire used for assessment of suicidal ideation and behavior with the following scale: 0: no ideation present; 1: wish to be dead; 2: non-specific active suicidal thoughts; 3: active suicidal ideation with any methods (not plan) without intent to act; 4: active suicidal ideation with some intent to act, without specific plan; 5: active suicidal ideation with specific plan and intent; 6: preparatory acts or behavior; 7: aborted attempt; 8: interrupted attempt; 9: actual attempt (non-fatal); 10: completed suicide.	Baseline through Day 28
Snakebite Severity score	SSS neurologic system subscore Baseline through Day 7	Baseline through day 7

Collaborators and Investigators

• Sponsor: Ophirex, Inc.
• Collaborators: Premier Research Group plc
• Investigators: Principal Investigator: Matthew Lewin, MD, PhD, Ophirex, Inc.; Principal Investigator: Timothy F Platts-Mills, MD, MSc, Ophirex, Inc.

Publications and helpful links

General Publications

• Varespladib. Am J Cardiovasc Drugs. 2011;11(2):137-43. doi: 10.2165/11533650-000000000-00000.
• Alangode A, Rajan K, Nair BG. Snake antivenom: Challenges and alternate approaches. Biochem Pharmacol. 2020 Nov;181:114135. doi: 10.1016/j.bcp.2020.114135. Epub 2020 Jul 3.
• Albulescu LO, Xie C, Ainsworth S, Alsolaiss J, Crittenden E, Dawson CA, Softley R, Bartlett KE, Harrison RA, Kool J, Casewell NR. A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite. Nat Commun. 2020 Dec 15;11(1):6094. doi: 10.1038/s41467-020-19981-6. Erratum In: Nat Commun. 2021 Jun 24;12(1):4027.
• Anderson BO, Moore EE, Banerjee A. Phospholipase A2 regulates critical inflammatory mediators of multiple organ failure. J Surg Res. 1994 Feb;56(2):199-205. doi: 10.1006/jsre.1994.1032.
• Arce-Bejarano R, Lomonte B, Gutierrez JM. Intravascular hemolysis induced by the venom of the Eastern coral snake, Micrurus fulvius, in a mouse model: identification of directly hemolytic phospholipases A2. Toxicon. 2014 Nov;90:26-35. doi: 10.1016/j.toxicon.2014.07.010. Epub 2014 Aug 1.
• Bittenbinder MA, Zdenek CN, Op den Brouw B, Youngman NJ, Dobson JS, Naude A, Vonk FJ, Fry BG. Coagulotoxic Cobras: Clinical Implications of Strong Anticoagulant Actions of African Spitting Naja Venoms That Are Not Neutralised by Antivenom but Are by LY315920 (Varespladib). Toxins (Basel). 2018 Dec 4;10(12):516. doi: 10.3390/toxins10120516.
• Bryan-Quiros W, Fernandez J, Gutierrez JM, Lewin MR, Lomonte B. Neutralizing properties of LY315920 toward snake venom group I and II myotoxic phospholipases A2. Toxicon. 2019 Jan;157:1-7. doi: 10.1016/j.toxicon.2018.11.292. Epub 2018 Nov 14.
• Bulfone TC, Samuel SP, Bickler PE, Lewin MR. Developing Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite. J Trop Med. 2018 Jul 30;2018:4320175. doi: 10.1155/2018/4320175. eCollection 2018.
• Chippaux JP. Estimate of the burden of snakebites in sub-Saharan Africa: a meta-analytic approach. Toxicon. 2011 Mar 15;57(4):586-99. doi: 10.1016/j.toxicon.2010.12.022. Epub 2011 Jan 9.
• Fernandez ML, Quartino PY, Arce-Bejarano R, Fernandez J, Camacho LF, Gutierrez JM, Kuemmel D, Fidelio G, Lomonte B. Intravascular hemolysis induced by phospholipases A2 from the venom of the Eastern coral snake, Micrurus fulvius: Functional profiles of hemolytic and non-hemolytic isoforms. Toxicol Lett. 2018 Apr;286:39-47. doi: 10.1016/j.toxlet.2017.11.037. Epub 2017 Nov 29.
• Fontana Oliveira IC, Gutierrez JM, Lewin MR, Oshima-Franco Y. Varespladib (LY315920) inhibits neuromuscular blockade induced by Oxyuranus scutellatus venom in a nerve-muscle preparation. Toxicon. 2020 Nov;187:101-104. doi: 10.1016/j.toxicon.2020.08.023. Epub 2020 Sep 2.
• Gerardo CJ, Vissoci JRN, Evans CS, Simel DL, Lavonas EJ. Does This Patient Have a Severe Snake Envenomation?: The Rational Clinical Examination Systematic Review. JAMA Surg. 2019 Apr 1;154(4):346-354. doi: 10.1001/jamasurg.2018.5069.
• Gutierrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA. Snakebite envenoming. Nat Rev Dis Primers. 2017 Sep 14;3:17063. doi: 10.1038/nrdp.2017.63. Erratum In: Nat Rev Dis Primers. 2017 Oct 05;3:17079.
• Gutierrez 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 Feb 20;12(2):131. doi: 10.3390/toxins12020131.
• Halilu S, Iliyasu G, Hamza M, Chippaux JP, Kuznik A, Habib AG. Snakebite burden in Sub-Saharan Africa: estimates from 41 countries. Toxicon. 2019 Mar 1;159:1-4. doi: 10.1016/j.toxicon.2018.12.002. Epub 2018 Dec 27.
• Kazandjian TD, Petras D, Robinson SD, van Thiel J, Greene HW, Arbuckle K, Barlow A, Carter DA, Wouters RM, Whiteley G, Wagstaff SC, Arias AS, Albulescu LO, Plettenberg Laing A, Hall C, Heap A, Penrhyn-Lowe S, McCabe CV, Ainsworth S, da Silva RR, Dorrestein PC, Richardson MK, Gutierrez JM, Calvete JJ, Harrison RA, Vetter I, Undheim EAB, Wuster W, Casewell NR. Convergent evolution of pain-inducing defensive venom components in spitting cobras. Science. 2021 Jan 22;371(6527):386-390. doi: 10.1126/science.abb9303.
• Le Geyt J, Pach S, Gutierrez JM, Habib AG, Maduwage KP, Hardcastle TC, Hernandez Diaz R, Avila-Aguero ML, Ya KT, Williams D, Halbert J. Paediatric snakebite envenoming: recognition and management of cases. Arch Dis Child. 2021 Jan;106(1):14-19. doi: 10.1136/archdischild-2020-319428. Epub 2020 Oct 28.
• 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 Aug 25;8(9):248. doi: 10.3390/toxins8090248.
• Lewin MR, Gilliam LL, Gilliam J, Samuel SP, Bulfone TC, Bickler PE, Gutierrez JM. Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom. Toxins (Basel). 2018 Nov 17;10(11):479. doi: 10.3390/toxins10110479.
• Lewin MR, Gutierrez JM, Samuel SP, Herrera M, Bryan-Quiros W, Lomonte B, Bickler PE, Bulfone TC, Williams DJ. Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom. Toxins (Basel). 2018 Sep 20;10(10):380. doi: 10.3390/toxins10100380.
• Longbottom J, Shearer FM, Devine M, Alcoba G, Chappuis F, Weiss DJ, Ray SE, Ray N, Warrell DA, Ruiz de Castaneda R, Williams DJ, Hay SI, Pigott DM. Vulnerability to snakebite envenoming: a global mapping of hotspots. Lancet. 2018 Aug 25;392(10148):673-684. doi: 10.1016/S0140-6736(18)31224-8. Epub 2018 Jul 17.
• Pach S, Le Geyt J, Gutierrez JM, Williams D, Maduwage KP, Habib AG, Gustin R, Avila-Aguero ML, Ya KT, Halbert J. Paediatric snakebite envenoming: the world's most neglected 'Neglected Tropical Disease'? Arch Dis Child. 2020 Dec;105(12):1135-1139. doi: 10.1136/archdischild-2020-319417. Epub 2020 Sep 30.
• PARRISH HM. SNAKE VENENATION IN ILLINOIS. IMJ Ill Med J. 1965 Jun;127:671-7. No abstract available.
• Prasarnpun S, Walsh J, Awad SS, Harris JB. Envenoming bites by kraits: the biological basis of treatment-resistant neuromuscular paralysis. Brain. 2005 Dec;128(Pt 12):2987-96. doi: 10.1093/brain/awh642. Epub 2005 Sep 29.
• Ruha AM, Kleinschmidt KC, Greene S, Spyres MB, Brent J, Wax P, Padilla-Jones A, Campleman S; ToxIC Snakebite Study Group. The Epidemiology, Clinical Course, and Management of Snakebites in the North American Snakebite Registry. J Med Toxicol. 2017 Dec;13(4):309-320. doi: 10.1007/s13181-017-0633-5. Epub 2017 Oct 3.
• Salvador GHM, Gomes AAS, Bryan-Quiros W, Fernandez J, Lewin MR, Gutierrez JM, Lomonte B, Fontes MRM. Structural basis for phospholipase A2-like toxin inhibition by the synthetic compound Varespladib (LY315920). Sci Rep. 2019 Nov 20;9(1):17203. doi: 10.1038/s41598-019-53755-5.
• Sankar J, Nabeel R, Sankar MJ, Priyambada L, Mahadevan S. Factors affecting outcome in children with snake envenomation: a prospective observational study. Arch Dis Child. 2013 Aug;98(8):596-601. doi: 10.1136/archdischild-2012-303025. Epub 2013 May 28.
• Schulte J, Domanski K, Smith EA, Menendez A, Kleinschmidt KC, Roth BA. Childhood Victims of Snakebites: 2000-2013. Pediatrics. 2016 Nov;138(5):e20160491. doi: 10.1542/peds.2016-0491.
• Seifert SA, Boyer LV, Benson BE, Rogers JJ. AAPCC database characterization of native U.S. venomous snake exposures, 2001-2005. Clin Toxicol (Phila). 2009 Apr;47(4):327-35. doi: 10.1080/15563650902870277.
• Snyder DW, Bach NJ, Dillard RD, Draheim SE, Carlson DG, Fox N, Roehm NW, Armstrong CT, Chang CH, Hartley LW, Johnson LM, Roman CR, Smith AC, Song M, Fleisch JH. Pharmacology of LY315920/S-5920, [[3-(aminooxoacetyl)-2-ethyl-1- (phenylmethyl)-1H-indol-4-yl]oxy] acetate, a potent and selective secretory phospholipase A2 inhibitor: A new class of anti-inflammatory drugs, SPI. J Pharmacol Exp Ther. 1999 Mar;288(3):1117-24.
• Sorensen J, Kald B, Tagesson C, Lindahl M. Platelet-activating factor and phospholipase A2 in patients with septic shock and trauma. Intensive Care Med. 1994 Nov;20(8):555-61. doi: 10.1007/BF01705721.
• Tasoulis T, Isbister GK. A Review and Database of Snake Venom Proteomes. Toxins (Basel). 2017 Sep 18;9(9):290. doi: 10.3390/toxins9090290.
• Uhl W, Beger HG, Hoffmann G, Hanisch E, Schild A, Waydhas C, Entholzner E, Muller K, Kellermann W, Vogeser M, et al. A multicenter study of phospholipase A2 in patients in intensive care units. J Am Coll Surg. 1995 Mar;180(3):323-31.
• Vaiyapuri S, Vaiyapuri R, Ashokan R, Ramasamy K, Nattamaisundar K, Jeyaraj A, Chandran V, Gajjeraman P, Baksh MF, Gibbins JM, Hutchinson EG. Snakebite and its socio-economic impact on the rural population of Tamil Nadu, India. PLoS One. 2013 Nov 21;8(11):e80090. doi: 10.1371/journal.pone.0080090. eCollection 2013.
• Williams DJ, Faiz MA, Abela-Ridder B, Ainsworth S, Bulfone TC, Nickerson AD, Habib AG, Junghanss T, Fan HW, Turner M, Harrison RA, Warrell DA. Strategy for a globally coordinated response to a priority neglected tropical disease: Snakebite envenoming. PLoS Negl Trop Dis. 2019 Feb 21;13(2):e0007059. doi: 10.1371/journal.pntd.0007059. eCollection 2019 Feb. No abstract available.
• Xie C, Albulescu LO, Bittenbinder MA, Somsen GW, Vonk FJ, Casewell NR, Kool J. Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins. Biomedicines. 2020 Aug 20;8(9):297. doi: 10.3390/biomedicines8090297.
• 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 May 29;12(6):356. doi: 10.3390/toxins12060356.

Helpful Links

• Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2021
• Primary Completion (Actual): June 7, 2023
• Study Completion (Actual): June 8, 2023

Study Registration Dates

• First Submitted: July 30, 2021
• First Submitted That Met QC Criteria: August 6, 2021
• First Posted (Actual): August 9, 2021

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 19, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: varespladib; LY333013; snakebite; envenoming; venom; snakebite severity score; snake; antidote; sPLA2
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Wounds and Injuries; Poisoning; Bites and Stings; Snake Bites; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Phospholipase A2 Inhibitors; Varespladib methyl
• Other Study ID Numbers: OPX-PR-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No