Tissue Factor Antagonists for ALI/ARDS

ALI/ARDS 的组织因子拮抗剂

• 批准号: 8495391
• 负责人: HING C. WONG
• 金额: $ 106.24万
• 依托单位: ALTOR BIOSCIENCE. LLC
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495391
• 关键词: Acute; Acute Lung Injury; Acute respiratory failure; Address; Adult Respiratory Distress Syndrome; Age; Agreement; Alveolar; American; Antibodies; Attenuated; Award; Bacteria; Binding; Biochemical; Biological; Bolus Infusion; Characteristics; Clinical; Clinical Research; Coagulation Process; Complex; Consensus; Critical Care; Cytoplasmic Tail; Data; Deposition; Disease; Disseminated Intravascular Coagulation; Dose; Double-Blind Method; Drug Kinetics; Enrollment; Environmental air flow; Escherichia coli; European; Evaluation; Event; Exhibits; Factor IX; Factor VIIa; Factor X; Fibrin; Funding; Future; Gases; Goals; Grant; Health Care Costs; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Intensive Care Units; Licensing; Liquid substance; Lung; Mediating; Medical; Medicine; Modeling; Monoclonal Antibodies; National Heart, Lung, and Blood Institute; Onset of illness; Oropharyngeal; Overdose; Pancreatitis; Parents; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase II Clinical Trials; Physicians; Physiological; Placebo Control; Plasma; Play; Population; Prevalence; Process; Proteinase-Activated Receptors; Public Health; Pulmonary Edema; Pulmonary Hypertension; Randomized; Recombinants; Regimen; Reporting; Respiratory Failure; Role; Safety; Sepsis; Septicemia; Serum; Signal Transduction; Small Business Innovation Research Grant; Source; Stimulus; Stomach; System; Testing; Therapeutic; Thromboplastin; Thrombus; Trauma; United States; Ventilator; blood product; chimeric antibody; clinical efficacy; clinically relevant; cytokine; hexachlorocyclohexane x-factor; interest; meetings; mortality; nonhuman primate; novel; preclinical study; prevent; protein activation; symposium; treatment duration

DESCRIPTION (provided by applicant): The pathogenesis of ALI/ARDS involves both procoagulant and inflammatory mechanisms. Extravascular fibrin deposition in the lung is a characteristic pathologic feature of ALI/ARDS and intra-alveolar thrombi develop in the lungs of patients with ALI/ARDS. Tissue factor (TF), the trigger protein for activation of the extrinsic coagulation pathway, has a direct role in promoting these effects as indicated by the elevated levels of TF observed in plasma of ALI/ARDS patients compared to control patients with hydrostatic pulmonary edema. These higher plasma TF levels correlated with increased mortality, fewer ventilator-free days, the presence of disseminated intravascular coagulation and the progression to sepsis in patients with ALI/ARDS, suggesting that systemic activation of coagulation may be clinically important in ALI/ARDS. Additionally, TF levels in pulmonary edema fluid from patients with ALI/ARDS were significantly higher than in control patients. In fact, pulmonary TF levels in patients with ALI/ARDS were found to be approximately 100-fold higher than corresponding plasma levels, suggesting an intra-alveolar source of TF. As a result, we have been interested in developing TF antagonists as a therapeutic strategy for treating ALI/ARDS and other inflammatory disorders. In an experimental E. coli sepsis-induced ALI model in non-human primates, we have shown that an anti-TF monoclonal antibody, ALT-836, could attenuate sepsis-induced abnormalities in gas exchange, pulmonary hypertension, and loss of pulmonary system compliance. The results from our pre-clinical studies prompted us to conduct a single-bolus, dose-escalating, Phase 1/2a trial followed by a 120-patient, 1:1 randomized, placebo-controlled Phase 2 clinical trial (with the option to adjust the dosing regimen after an interim analysis of the first 60 enrolled ALI/ARDS patients). The results of the 18-patient Phase 1/2a trial and first 60 patients of the Phase 2 trial indicated that ALT-836 exhibits favorable pharmacokinetic and pharmacodynamic profiles and is well tolerated at the dose level of 0.06 mg/kg as a single bonus infusion. Analysis of the Phase 2 interim data also suggests that single-dose ALT-836 treatment provides beneficial effects to patients during the first one-two weeks of the treatment period. Thus, an independent study is warranted to examine whether the clinical and biological effects observed with single dose regimen could be extended with multiple doses. Under this SBIR Phase II Competing Renewal proposal, we intend to conduct a 90-patient, 1:1 randomized, placebo-controlled Phase 2 clinical trial to examine the safety, pharmacokinetics and efficacy of multi-dose administration of ALT-836 at the 0.06 mg/kg dose level in patients with sepsis-induced ALI/ARDS. Altor also has an in-licensing agreement in place with Genentech for this product and anticipates that positive clinical results from the proposed study will prompt Genentech to sponsor a large Phase 3 registration trial for regulatory approval of ALT-836 by the US FDA.

描述（由申请人提供）：ALI/ARDS的发病机制涉及促凝血和炎症机制。肺内血管外纤维蛋白沉积是ALI/ARDS的特征性病理特征，并且ALI/ARDS患者的肺内形成肺泡内血栓。组织因子（TF）是激活外源性凝血途径的触发蛋白，在促进这些效应中具有直接作用，如在ALI/ARDS患者的血浆中观察到的TF水平升高所示，与对照的流体静力性肺水肿患者相比。这些较高的血浆TF水平与ALI/ARDS患者的死亡率增加、无呼吸机天数减少、弥散性血管内凝血的存在和脓毒症的进展相关，表明全身凝血激活在ALI/ARDS中可能具有临床重要性。此外，ALI/ARDS患者肺水肿液中TF水平显著高于对照组。事实上，发现ALI/ARDS患者的肺TF水平比相应的血浆水平高约100倍，表明TF的肺泡内来源。因此，我们一直有兴趣开发TF拮抗剂作为治疗ALI/ARDS和其他炎症性疾病的治疗策略。在实验性E.在非人灵长类动物中的大肠杆菌败血症诱导的ALI模型中，我们已经表明抗TF单克隆抗体ALT-836可以减弱败血症诱导的气体交换、肺动脉高压和肺系统顺应性丧失的异常。临床前研究的结果促使我们进行了一项单次推注、剂量递增的I/IIa期试验，随后进行了一项120例患者、1：1随机化、安慰剂对照的II期临床试验（在对前60例入组的ALI/ARDS患者进行中期分析后，可以选择调整给药方案）。18例患者的I/IIa期试验和II期试验的前60例患者的结果表明，ALT-836表现出良好的药代动力学和药效学特征，并且在0.06 mg/kg剂量水平下作为单次额外输注耐受良好。II期中期数据的分析还表明，单剂量ALT-836治疗在治疗期的前1 - 2周内为患者提供了有益效果。因此，有必要进行一项独立研究，以检查单次给药方案观察到的临床和生物学效应是否可以通过多次给药延长。根据SBIR II期竞争性更新提案，我们打算进行一项90例患者、1：1随机、安慰剂对照的II期临床试验，以检查在脓毒症诱导的ALI/ARDS患者中以0.06 mg/kg剂量水平多次给药ALT-836的安全性、药代动力学和疗效。Altor还与Genentech就该产品达成了许可协议，并预计拟议研究的积极临床结果将促使Genentech赞助一项大型3期注册试验，以获得美国FDA对ALT-836的监管批准。

项目成果

Inhibition of acute vascular thrombosis in chimpanzees by an anti-human tissue factor antibody targeting the factor X binding site.

• DOI: 10.1160/th09-06-0400
• 发表时间: 2010-01
• 期刊: Thrombosis and haemostasis
• 影响因子: 6.7
• 作者: Jiao JA;Kelly AB;Marzec UM;Nieves E;Acevedo J;Burkhardt M;Edwards A;Zhu XY;Chavaillaz PA;Wong A;Wong JL;Egan JO;Taylor D;Rhode PR;Wong HC
• 通讯作者: Wong HC

A phase I study evaluating the pharmacokinetics, safety and tolerability of an antibody-based tissue factor antagonist in subjects with acute lung injury or acute respiratory distress syndrome.

• DOI: 10.1186/1471-2466-12-5
• 发表时间: 2012-02-16
• 期刊: BMC pulmonary medicine
• 影响因子: 3.1
• 作者: Morris PE;Steingrub JS;Huang BY;Tang S;Liu PM;Rhode PR;Wong HC
• 通讯作者: Wong HC