Treatment of Surgical Sepsis with AM/AMBP-1

AM/AMBP-1 治疗手术脓毒症

• 批准号: 7684827
• 负责人: RONGQIAN WU
• 金额: $ 43.4万
• 依托单位: THERASOURCE, LLC
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684827
• 关键词: Adverse effects; Affect; Animals; Area Under Curve; Attenuated; Binding Proteins; Biological; Blood Vessels; Body Weight; Budgets; Cardiovascular Physiology; Cardiovascular system; Caring; Cause of Death; Cecum; Clinical Trials; Coagulation Process; Data; Development; Dose; Drug Kinetics; Economic Burden; Epidemiologic Studies; Evaluation; FDA approved; Family suidae; Figs - dietary; Future; Goals; Half-Life; Healthcare; Human; Human Development; Infection; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Intensive Care Units; Investigation; Label; Life; Ligation; Lilly brand of drotrecogin alfa activated; Marketing; Measures; Medical; Modeling; Monitor; Necrosis; Operative Surgical Procedures; Organ; Patients; Peptides; Perfusion; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Production; Property; Puncture procedure; Radioactive; Rat Protein; Rattus; Reporting; Research; Rodent Model; Sepsis; Septic Shock; Serum; Small Business Innovation Research Grant; Staging; Survival Rate; Technology; Therapeutic Agents; Time; Tissues; Trauma; United States; Work; activated Protein C; adrenomedullin; cardiovascular injury; cost; cytokine; dosage; drotrecogin alfa; drug clearance; effective therapy; hemodynamics; human adrenomedullin-binding protein 1; immunogenicity; implantation; improved; mortality; novel; novel therapeutic intervention; pre-clinical; preclinical study; public health relevance; response; scale up; septic

DESCRIPTION (provided by applicant): This SBIR Phase II proposal is a plan to further develop a new therapeutic approach that will save the lives of patients with sepsis (especially surgical sepsis), a condition that affects 750,000 people every year in the United States alone and also causes high mortality worldwide. Although activated protein C [APC, Drotrecogin alpha (activated), Xigris. marketed by Eli Lilly] is the only FDA- approved specific treatment for sepsis, it cannot be used in surgical patients with sepsis due to its adverse effects on coagulation. Thus, there is an even greater need for an effective novel treatment for surgical sepsis. Successful development of a new anti-sepsis therapy will not only have a positive impact on health care, but it will also have highly significant commercial benefits. The global market potential for sepsis treatment is estimated at over $30 billion annually. We have recently discovered that vascular responsiveness to adrenomedullin (AM), a newly-reported potent vasoactive peptide, decreases during sepsis in the rat and is markedly improved by its novel binding protein (i.e., AMBP-1). Treatment with rat AM combined with human AMBP-1 improved cardiovascular function, attenuated tissue injury and inflammatory responses, and reduced mortality in a rat cecal ligation and puncture (CLP, induced by surgery) model of sepsis, suggesting that AM/AMBP-1 may be an effective treatment for human sepsis. One obstacle hampering the development of AM/AMBP-1 as a therapeutic agent for sepsis is the potential immunogenicity of rat proteins in humans. In this regard, the primary objective of our Phase I proposal was to determine the effect of human AM/AMBP-1 on sepsis-induced organ injury, inflammation, and mortality. We have achieved these milestones using the rat CLP model of sepsis. In the Phase I project, we have clearly demonstrated the efficacy of human AM/AMBP-1 and thereby established the technical merit and feasibility of the proposed Phase II project. However, the extremely high cost of commercial human AMBP- 1 limits the further development of human AM/AMBP-1 as an anti-sepsis therapy. To overcome this difficulty, we have successfully isolated and purified AMBP-1 from normal human serum at a much lower cost. We therefore continue to hypothesize that the administration of human AM/AMBP-1 late after the onset of sepsis attenuates tissue injury and improves survival. In this Phase II proposal, we will first, scale up the production of human AMBP-1 and, then, perform additional efficacy studies in order to determine the optimal protective dosage of human AM/AMBP-1 in sepsis in the rat. Moreover, the pharmacokinetic characterization of human AM/AMBP-1 in sepsis will be assessed. To advance our technology to the clinical trials, the efficacy of human AM/AMBP-1 will be investigated in a swine model of sepsis. These proposed studies should provide sufficient preclinical data that will allow us to file an IND application to the FDA to initiate clinical trials in order to obtain the commercial utilization of human AM/AMBP-1 as a safe and effective therapy for patients with sepsis, especially those who develop sepsis after trauma or major surgery. PUBLIC HEALTH RELEVANCE Sepsis is one of the leading causes of death in most intensive care units. Over 210,000 people succumb to this overwhelming infection in the United States annually. A recent epidemiologic study estimated that about 750,000 people develop sepsis each year at a cost of $16.7 billion nationally. Given the intensive and prolonged care necessary to treat patients with sepsis, the economic burden is profound. Thus, there is an urgent unmet medical need for an effective novel therapy for septic patients.

描述（由申请人提供）：这项 SBIR II 期提案是一项进一步开发新治疗方法的计划，该方法将挽救脓毒症（尤其是手术脓毒症）患者的生命，这种疾病仅在美国每年就影响 750,000 人，并在全世界造成高死亡率。虽然活化蛋白 C [APC、Drotrecogin α（活化）、Xigris。礼来公司销售的]是FDA批准的唯一治疗脓毒症的特效药物，但由于其对凝血的不良影响，不能用于脓毒症的手术患者。因此，更需要一种有效的新型手术脓毒症治疗方法。成功开发一种新的抗脓毒症疗法不仅会对医疗保健产生积极影响，而且还将产生非常显着的商业利益。脓毒症治疗的全球市场潜力估计每年超过 300 亿美元。我们最近发现，在大鼠脓毒症期间，血管对肾上腺髓质素（AM）（一种新报道的强效血管活性肽）的反应性降低，并且其新型结合蛋白（即 AMBP-1）显着改善。大鼠AM联合人AMBP-1治疗可改善大鼠盲肠结扎穿刺（CLP，手术诱导）脓毒症模型的心血管功能，减轻组织损伤和炎症反应，并降低死亡率，表明AM/AMBP-1可能是治疗人脓毒症的有效方法。阻碍 AM/AMBP-1 作为败血症治疗剂开发的一个障碍是大鼠蛋白在人类中的潜在免疫原性。在这方面，我们第一阶段提案的主要目标是确定人类 AM/AMBP-1 对脓毒症引起的器官损伤、炎症和死亡率的影响。我们使用脓毒症大鼠 CLP 模型实现了这些里程碑。在第一阶段项目中，我们清楚地证明了人类AM/AMBP-1的功效，从而确定了拟议第二阶段项目的技术优点和可行性。然而，商业化人AMBP-1的极高成本限制了人AM/AMBP-1作为抗脓毒症疗法的进一步发展。为了克服这一困难，我们以较低的成本成功地从正常人血清中分离纯化了 AMBP-1。因此，我们继续假设脓毒症发病后期施用人 AM/AMBP-1 可减轻组织损伤并提高生存率。在此 II 期提案中，我们将首先扩大人 AMBP-1 的生产，然后进行额外的功效研究，以确定人 AM/AMBP-1 在大鼠脓毒症中的最佳保护剂量。此外，还将评估脓毒症中人 AM/AMBP-1 的药代动力学特征。为了将我们的技术推进到临床试验，我们将在脓毒症猪模型中研究人类 AM/AMBP-1 的功效。这些拟议的研究应该提供足够的临床前数据，使我们能够向 FDA 提交 IND 申请，启动临床试验，以获得人类 AM/AMBP-1 的商业用途，作为脓毒症患者的安全有效的治疗方法，特别是那些在创伤或大手术后发生脓毒症的患者。公共卫生相关性脓毒症是大多数重症监护病房的主要原因之一。在美国，每年有超过 210,000 人死于这种压倒性的感染。最近的一项流行病学研究估计，每年约有 75 万人患上败血症，全国损失达 167 亿美元。鉴于治疗脓毒症患者所需的强化和长期护理，经济负担是巨大的。因此，对于脓毒症患者的有效新疗法存在迫切的未满足的医疗需求。