Development of Intravenous Varespladib, a Phospholipase A2 Inhibitor, for the Treatment of Snakebite Envenoming

1项目概要 2 3在实验研究中，直接抑制蛇毒毒素分泌型磷脂酶A2（sPLA 2）的结果 4显著改善sPLA 2介导的毒性，但sPLA 2抑制在人类咬伤中的益处 5、蛇是未知的。Ophirex是一家公益公司，其使命是减少死亡， 6通过开发伐瑞拉迪（一种高效的 7蛇毒sPLA 2。蛇毒sPLA 2和sPLA 2样蛋白存在于95%的医学上重要的 世界上有8种毒蛇，被认为存在于所有原产于美国的毒蛇中。这些 9种蛋白质是神经肌肉麻痹、凝血病、心脏毒性、肾毒性和骨骼肌毒性的关键因素。 10肌肉损伤抗体疗法（“抗蛇毒血清”）对sPLA 2具有有限的功效，因为通常 11. sPLA 2的低抗原性和由于生理屏障抗体进入重要的 12个隔室（例如，肌肉、神经运动接头）。Varespladib已被发现可以拯救小鼠和猪， 13致命的envenoming从各种各样的蛇，即使在一个时间点，当抗蛇毒血清是没有 第14话拯救动物伐瑞拉迪也与抗蛇毒血清协同作用：在临床前研究中， 伐瑞拉迪和抗蛇毒血清的组合导致对sPLA 2的更大抑制和更大的保护作用。 16从一系列sPLA 2介导的毒性中获益，而不是从汇总 17、两种治疗方法该项目的总体目标是进行研究，以支持监管 18批准伐瑞拉迪静脉制剂用于SBE。这将通过完成以下工作来实现： 19一项在110名毒蛇咬伤患者中进行的伐瑞拉迪IIb期双盲随机对照试验 20岁，在美国和印度接受治疗。所有患者将接受标准治疗，包括 21抗蛇毒血清患者将接受伐瑞拉迪或生理盐水连续输注至少6小时。后 当患者临床稳定并能够耐受口服药物后22 6小时， 23例口服伐瑞拉迪或安慰剂治疗。治疗的总持续时间为7天。主 结果将是从基线到3小时和6小时蛇咬伤严重程度评分平均值的变化， 25评估血液学、神经学、肾、心血管和肺的关键蛇毒毒性。 26个系统。拟议的工作还将利用两种创新方法来扩大试验结果 （1）将使用基于生理学的药代动力学建模来确定 28种儿科患者的适当给药策略，以增强可用的儿科安全性和疗效数据;以及 29（2）将使用模拟模型评估伐瑞拉迪在被蛇咬伤患者中的临床效果 第30章在审判中不被看好拟议工作的结果将用于支持监管审批 31有可能改变蛇咬伤治疗的范例，每年拯救数千人的生命。

1 Project Summary 2 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.