Development of Intravenous Varespladib, a Phospholipase A2 Inhibitor, for the Treatment of Snakebite Envenoming - 1 Project Summary
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3 In experimental studies, direct inhibition of the snake venom toxin secretory phospholipase A2 (sPLA2) results
4 in significant improvements in sPLA2-mediated toxicities, but the benefits of sPLA2 inhibition in humans bitten
5 by snakes remains unknown. Ophirex is a Public Benefit Corporation whose mission is to reduce death and
6 disability from snakebite envenoming (SBE) through the development of varespladib, a highly potent inhibitor of
7 snake venom sPLA2. Snake venom sPLA2 and sPLA2-like proteins are found in 95% of medically important
8 venomous snakes worldwide and thought to be found in all venomous snakes native to the United States. These
9 proteins are key contributors to neuromuscular paralysis, coagulopathy, cardiotoxicity, renal toxicity, and skeletal
10 muscle injury. Antibody therapies (“antivenoms”) have limited efficacy against sPLA2 because of the generally
11 low antigenicity of sPLA2 and because of physiologic barriers to the entry of antibodies into important
12 compartments (e.g., muscle, neuromotor junctions). Varespladib has been found to rescue mice and pigs from
13 lethal envenoming from a variety of species of snake, even when given at a point in time when antivenom is no
14 longer able to rescue the animals. Varespladib also acts synergistically with antivenom: In preclinical studies,
15 the combination of varespladib and antivenom results in greater inhibition of sPLA2 and greater protective
16 benefits from a range of sPLA2-mediated toxicities than would be expected from summing the benefits of the
17 two therapies on their own. The overarching goal of this project is to conduct research to support regulatory
18 approval of an intravenous formulation of varespladib for SBE. This will be achieved through the completion of
19 a Phase IIb double-blind randomized controlled trial of varespladib in 110 patients bitten by venomous snakes
20 and receiving care at sites in the U.S. and India. All patients will receive standard of care treatment, including
21 antivenom. Patients will receive a continuous infusion of varespladib or normal saline for at least 6 hours. After
22 6 hours of whenever they are clinically stable and able to tolerate oral medication, patients will be switched to
23 oral treatment with varespladib-methyl or placebo. The total duration of treatment will be 7 days. The primary
24 outcome will be the change from baseline to the average at 3 and 6 hours of the Snakebite Severity Score, which
25 assesses key snake venom toxicities of the hematologic, neurologic, renal, cardiovascular, and pulmonary
26 systems. The proposed work will also utilize two innovative approaches to expanding the findings from the trial
27 to other important populations: (1) Physiologically-based pharmacokinetic modeling will be used to identify an
28 appropriate dosing strategy in pediatric patients and to enhance available pediatric safety and efficacy data; and
29 (2) A simulation model will be used to estimate the clinical effect of varespladib in patients bitten by snake species
30 not well-represented in the trial. The results of the proposed work will be used to support regulatory approval
31 with the potential to transform the paradigm for snakebite treatment and to save thousands of lives each year.
