Broad-spectrum Rapid Antidote: Varespladib Oral for Snakebite

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.

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).

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.