Bacterial-Induced Sepsis: A New Treatment Strategy

细菌引起的脓毒症：一种新的治疗策略

• 批准号: 8402570
• 负责人: SHARON L MCCOY
• 金额: $ 99.94万
• 依托单位: 13THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8402570
• 关键词: Address; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Area; Bacteria; Biological Assay; Biological Markers; Clinical; Clinical Protocols; Clinical Treatment; Clinical Trials; Clinical Trials Design; Contracts; Data; Detection; Development; Disease; Dose; Drug Approval; Drug Kinetics; Gene Delivery; Goals; Grant; Human; Immune response; Infection Control; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Length; Life; Ligation; Measures; Medical; Modeling; Morbidity - disease rate; Organ failure; Patients; Peptides; Pharmacology; Phase; Phase I Clinical Trials; Positioning Attribute; Pre-Clinical Model; Puncture procedure; Receptor Signaling; Research Contracts; Safety; Schedule; Sepsis; Serum; Small Business Innovation Research Grant; Survival Rate; Therapeutic; Time; Tissues; Toll-like receptors; Toxic effect; Toxicity Tests; Toxicology; Treatment Protocols; assay development; base; cell determination; clinical efficacy; clinically relevant; efficacy testing; improved; in vivo; inhibitor/antagonist; model development; mortality; novel; novel therapeutics; pre-clinical; public health relevance; research clinical testing; research study; response; safety testing; treatment strategy

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.

描述（由申请人提供）：败血症是一种普遍且威胁生命的医疗状况，其特征是发育失调的炎症免疫反应和相关的组织损伤。这种失调的炎症反应是通过响应细菌和/或细菌产物（例如LPS）激活Toll样受体（TLR）信号传导引发的。当前的治疗方法是有限的，涉及使用抗生素来控制感染和支持措施以帮助多器官衰竭患者。需要采取新的治疗策略来解决败血症患者的免疫反应失调，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型肽，该肽称为P13，这是一种有效但临时的细胞内TLR信号传导的抑制剂。根据当前II期SBIR赠款进行的研究i）证明，p13是在低剂量和高剂量LPS​​的动物体内体内血清炎症介质的有效抑制剂，ii）确定了p13的功效，以显着提高生存率的生存率，以增强lethal高剂量LPS​​诱导的模型，III III的生存率，III III II II III III效率）。在试验实验中证明了与临床相关的CECAL结扎和穿刺（CLP）多生物败血症模型，而IV）p13具有良好的安全性。 p13在开始全身炎症和疾病后给药时，在这些模型中提高了30-50％的生存率，而对照治疗的动物中的生存率为0％。此II期更新应用的主要目标是完成FDA所需的所有临床前功效和安全性测试，以批准该肽作为人类临床试验中的新治疗方法。基于我们的研究表明，p13在败血症前临床模型中提高生存率的功效和证明安全性概况的数据，我们在此II阶段续签应用中建议进行FDA所需的所有必要的研究，以将P13定位为人类临床试验。这些研究将包括在CLP模型中建立最佳的p13治疗参数，并开发用于血清和组织中p13的敏感测定法（特定目标＃1）。这些研究将支持适当的P13剂量和暴露参数，以供FDA进行药物批准所需的辅助研究。为了支持向FDA提交给P13的药物批准的IND，将确定最佳的临床治疗方案和与P13治疗相关的生物学标志物的鉴定（具体目标＃2）。将对P13进行详细的辅助研究，提供完整的非临床药理学，药代动力学和毒理学数据包（特定AIM＃3）。在此阶段II续签应用结束时，将向FDA提交IND，以在I期人类临床试验中使用p13。