Tissue Factor Antagonists for ALI/ARDS

描述（由申请人提供）：ALI/ARDS的发病机制涉及促凝剂和炎症机制。肺血管外纤维蛋白沉积是ALI/ARDS的一个特征性病理特征，ALI/ARDS患者肺部可出现肺泡内血栓。组织因子（TF）是激活外源性凝血途径的触发蛋白，在促进这些作用中起直接作用，ALI/ARDS患者血浆中观察到的TF水平高于对照组静液性肺水肿患者。这些较高的血浆TF水平与ALI/ARDS患者死亡率增加、无呼吸机天数减少、弥散性血管内凝血的存在以及败血症的进展相关，表明全身凝血激活可能在ALI/ARDS中具有重要的临床意义。此外，ALI/ARDS患者肺水肿液中的TF水平显著高于对照组。事实上，ALI/ARDS患者的肺TF水平比相应的血浆水平高出约100倍，提示肺泡内的TF来源。因此，我们一直对开发TF拮抗剂作为治疗ALI/ARDS和其他炎症性疾病的治疗策略感兴趣。在实验性大肠杆菌脓毒症诱导的非人类灵长类动物ALI模型中，我们已经证明抗tf单克隆抗体ALT-836可以减轻脓毒症引起的气体交换异常、肺动脉高压和肺系统顺应性丧失。临床前研究的结果促使我们进行了一项单剂量、剂量递增的1/2a期试验，随后进行了一项120例患者、1:1随机、安慰剂对照的2期临床试验（在对首批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1/2a期试验和首批60例患者的2期试验结果表明，ALT-836具有良好的药代动力学和药效学特征，并且在0.06 mg/kg的单次额外输注剂量水平下具有良好的耐受性。对2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周为患者提供有益效果。因此，有必要进行一项独立研究，以检验单次给药方案观察到的临床和生物学效应是否可以在多次给药时延长。根据SBIR II期竞争更新提案，我们打算开展一项90例患者、1:1随机、安慰剂对照的II期临床试验，以检查以0.06 mg/kg剂量水平多剂量给药ALT-836对败血症诱导的ALI/ARDS患者的安全性、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。

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.