Eritoran (E5564), a TLR4 antagonist, as a novel therapeutic for influenza

描述(申请人提供)：季节性流感与全球范围内的重大死亡率有关，但来自不同物种的流感毒株之间的基因组重新组合意外产生的大流行毒株可能会导致大流行和全球破坏。尽管针对流感的疫苗接种是有效的，但预测哪些抗原表位可能在下一个流感季节出现的科学是不精确的，而且可能会受到制造和分销的后勤问题的进一步影响。抗病毒药物，如神经氨酸酶抑制剂(NAIs)，由于许多流感病毒株对此类药物的抗药性不断增强，以及需要在感染后立即给予，而阻碍了此类药物的使用。这两种方法都侧重于针对病毒，而不是宿主对感染的反应。Imai等人提供的证据。(2008)提出，化学或微生物损伤引起的急性肺损伤(ALI)会引起氧化应激，导致氧化磷脂OxPAPC的产生，OxPAPC是Toll样受体4(TLR4)诱导的肺部炎症的有效激动剂。这一观察结果在PIS的实验室通过实验得到扩展，在这些实验中，TLR4靶向突变的小鼠被证明对小鼠适应的流感病毒株A/PR/8/24(“PR8”)感染高度耐药。需要检验的中心假设是，通过治疗阻断TLR4信号将预防流感感染。我们在我们的提案中提供了令人信服的证据，证明由Eisai Inc.生产的合成TLR4拮抗剂厄立特里亚(E5564)在人类1-3期临床试验中具有良好的安全性记录，在治疗时可以阻止小鼠的流感感染，甚至晚于抗病毒治疗所需的时间。拟议的计划是卫材公司与马里兰大学医学院、西格莫夫生物系统公司和马里兰大学兽医学院之间的伙伴关系，以优化厄立特里亚和非流感病毒的治疗，将其作为流感感染的治疗药物，利用小鼠优化治疗方案，并进一步说明流感感染和厄立特里亚对先天性免疫反应的影响，在棉花大鼠中探索对抗未适应的人类病毒株的效力，并在老年/免疫受损动物模型中，最后在雪貂中，确认并扩大在ABSL3条件下使用厄立特里亚大流行流感毒株的使用。提出了一项产品开发计划，其中描述了将厄立特里亚作为一种流感疗法转移到临床试验的未来计划。

DESCRIPTION (provided by applicant): Seasonal influenza is associated with significant mortality worldwide, but pandemic strains that arise unexpectedly from genomic reassortment between influenza strains from diverse species can lead to pandemics and global devastation. While vaccination against influenza is effective, the science of predicting which antigenic epitopes are likely to appear in the next influenza season is an imprecise one and can be further compromised by logistical problems of manufacturing and distribution. Antiviral agents, such as neuraminidase inhibitors (NAIs), are hampered by the increasing resistance of many influenza strains to such agents and the need to be administered very soon after infection. Both of these approaches focus on targeting the virus, rather than the host response to infection. Evidence by Imai et al. (2008) suggested that acute lung injury (ALI) caused by chemical or microbial insults causes oxidative stress that results in generation of an oxidized phospholipid, OxPAPC, a potent agonist of Toll-like Receptor 4 (TLR4)-induced lung inflammation. This observation was extended in the laboratories of the PIs by experiments in which mice with a targeted mutation in TLR4 were shown to be highly refractory to infection with mouse-adapted influenza strain A/PR/8/24 ("PR8"). The central hypothesis to be tested is that blocking TLR4 signaling therapeutically will protect against influenza infection. We provide compelling evidence in our proposal that the synthetic TLR4 antagonist, Eritoran (E5564), produced by Eisai Inc., and shown to have an excellent safety record in humans through Phase 1-3 clinical trials, blocks influenza infection in mice when administered therapeutically, even later than required for antiviral administration. The proposed plan is a partnership between Eisai Inc. and the University of Maryland, School of Medicine, Sigmovir Biosystems, Inc., and University of Maryland, College of Veterinary Medicine to optimize treatment with Eritoran and NAIs as a therapeutic for influenza infection using mice to optimize treatment regimens and further delineate the effect of influenza infection and Eritoran on the innate immune response, cotton rats to explore efficacy against non-adapted human strains of virus and in a model of aged/immunocompromised animals, and finally, in ferrets, to confirm and extend the use of Eritoran using pandemic strains of influenza under ABSL3 conditions. A Product Development Plan is presented that delineates future plans for moving Eritoran to clinical trial as a therapeutc for influenza.