Bacterial-Induced Sepsis: A New Treatment Strategy

描述（由申请人提供）：败血症是一种常见的危及生命的疾病，其特征是炎症免疫反应失调和相关组织损伤。这种失调的炎症反应是由toll样受体（TLR）信号的激活引起的，该信号是对细菌和/或细菌产物（如LPS）的反应。目前的治疗是有限的，包括使用抗生素来控制感染和支持措施来帮助多器官衰竭患者。需要新的治疗策略来解决败血症患者中出现的失调免疫反应，从而限制组织损伤并提高生存率。我们已经确定并表征了一种新的肽，称为P13，一种有效的细胞内TLR信号的暂时抑制剂。在目前的SBIR II期资助下进行的研究表明，1)在低剂量和高剂量LPS治疗的动物中，P13是一种有效的体内血清炎症媒介抑制剂，2)在致死性高剂量LPS诱导的脓毒症模型中，P13可以显著提高生存率，3)在临床相关的盲肠结扎和穿刺（CLP）多微生物脓毒症模型中，P13可以提高生存率。iv)在试点实验中证明P13具有良好的安全性。在全身性炎症和疾病开始后给予P13，可使这些模型的存活率提高30-50%，而对照组动物的存活率为0%。该II期续期申请的主要目标是完成FDA批准该肽作为人类临床试验新疗法所需的所有临床前疗效和安全性测试。基于我们的研究显示P13在脓毒症临床前模型中提高生存率的有效性，以及显示良好安全性的数据，我们建议在该II期续期申请中进行FDA要求的所有必要研究，以将P13用于人体临床试验。这些研究将包括在CLP模型中建立最佳的P13治疗参数，以及开发一种检测血清和组织中P13的敏感检测方法（具体目标1）。这些研究将为FDA批准药物所需的ind研究提供适当的P13剂量和暴露参数。为了支持向FDA提交P13药物批准的IND申请，将确定最佳临床治疗方案和与P13治疗相关的生物标志物的鉴定（具体目标#2）。将对P13进行详细的ind启用研究，提供完整的非临床药理学、药代动力学和毒理学数据包（具体目标#3）。在II期续期申请结束时，将向FDA提交一份IND，用于P13在I期人体临床试验中使用。

DESCRIPTION (provided by applicant): Sepsis is a prevalent and life-threatening medical condition characterized by development of a dysregulated inflammatory immune response and associated tissue damage. This dysregulated inflammatory response is initiated by activation of Toll-Like receptor (TLR) signaling in response to bacteria and/or bacterial products, such as LPS. Current treatments are limited and involve the use of antibiotics to control infection and supportive measures to assist patients with multi-organ failure. New treatment strategies are needed to address the dysregulated immune response seen in patients with sepsis, thereby limiting tissue damage and enhancing survival rates. We have identified and characterized a novel peptide, termed P13, a potent yet temporary inhibitor of intracellular TLR signaling. Studies performed under the current Phase II SBIR grant have i) demonstrated that P13 is a potent inhibitor of in vivo serum inflammatory mediators in animals administered both low-dose and high-dose LPS, ii) established the efficacy of P13 to significantly enhance survival rates in a lethal high-dose LPS-induced model of sepsis, iii) established the efficacy of P13 to enhance survival rates in the clinically relevant cecal ligation and puncture (CLP) polymicrobial sepsis model, and iv) demonstrated in pilot experiments a favorable safety profile for P13. P13, when administered after initiation of systemic inflammation and disease, improved the survival rate in these models 30-50% as compared with 0% survival in control treated animals. The primary goal of this Phase II Renewal Application is to complete all pre-clinical efficacy and safety testing required by the FDA for approval of this peptide as a new therapeutic in human clinical trials. Based on our studies showing efficacy of P13 to improve survival rates in sepsis pre- clinical models and data demonstrating a favorable safety profile, we propose in this Phase II Renewal Application to conduct all necessary studies required by the FDA to position P13 for human clinical trials. These studies will include establishing optimal P13 treatment parameters in the CLP model and development of a sensitive assay for detection of P13 in serum and tissues (specific aim #1). These studies will support appropriate P13 dosing and exposure parameters for the IND-enabling studies required by the FDA for drug approval. In support of the IND filing to the FDA for drug approval of P13, an optimal clinical treatment protocol and identification of biologic markers associated with P13 treatment will be determined (specific aim #2). Detailed IND-enabling studies for P13, providing a complete non-clinical pharmacology, pharmacokinetic, and toxicology data package will be performed (specific aim #3). At the conclusion of this Phase II Renewal Application an IND will be filed with the FDA for use of P13 in a Phase I human clinical trial. PUBLIC HEALTH RELEVANCE: New treatment options are needed for patients with bacterial-induced sepsis, a disease with increasing morbidity and mortality. We have identified a novel anti-inflammatory peptide that has demonstrated efficacy to limit inflammation and increase survival rates in an animal model of polymicrobial sepsis. Our current studies will complete all pre-clinical and safety testing required for FDA approval of this peptide to initiate human clinical trials as a new treatment for sepsis.