Tissue Factor Antagonists for ALI/ARDS

描述(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的典型病理特征，肺泡内血栓形成于ALI/ARDS患者的肺部。组织因子(Tf)是激活外源性凝血途径的触发蛋白，与对照组相比，ALI/ARDS患者血浆中的组织因子水平升高，表明组织因子在促进这些作用方面具有直接作用。这些升高的血浆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向脓毒症的进展相关，提示全身凝血功能的激活在ALI/ARDS中可能具有重要的临床意义。ALI/ARDS患者肺水肿液中Tf水平显著高于对照组。事实上，ALI/ARDS患者的肺组织因子水平约为相应血浆水平的100倍，提示肺组织因子来源于肺泡内。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策略感兴趣。在实验性大肠杆菌败血症诱导的非人灵长类动物ALI模型中，我们已经证明抗转铁蛋白单抗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的丧失。我们临床前研究的结果促使我们进行了单剂、剂量递增的1/2a期试验，随后进行了120名患者、1：1随机、安慰剂对照的2期临床试验(在对前60名入选的ALI/ARDS患者进行中期分析后，可以选择调整给药方案)。18名患者的1/2a期试验和2期试验的前60名患者的结果表明，ALT-836表现出良好的药代动力学和药效学特征，作为单次额外输注，在0.06 mg/kg的剂量水平下耐受性良好。对第二阶段中期数据的分析还表明，单剂ALT-836治疗在治疗期的头一到两周内为患者提供了有益的效果。因此，有必要进行一项独立的研究，以检查单剂方案观察到的临床和生物学效应是否可以延长到多剂。根据这项SBIR第二阶段竞争性更新建议，我们打算进行一项有90名患者、1：1随机、安慰剂对照的第二阶段临床试验，以检查多剂量给予ALT-836 0.06 mg/kg剂量水平对脓毒症所致ALI/ARDS患者的安全性、药代动力学和疗效。Altor还与Genentech签订了该产品的内部许可协议，并预计拟议研究的积极临床结果将促使Genentech赞助一项大型第三阶段注册试验，以获得美国FDA对ALT-836的监管批准。 公共卫生相关性：这项建议的目标是评估一种新的抗组织因子单抗ALT-836在90名患者中治疗急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)的临床实用性，该研究采用多剂量方案，随机、安慰剂对照、双盲、多中心2期临床研究。如果这项试验成功地达到其临床疗效终点，ALT-836将在监管部门批准所需的关键阶段3注册试验中进行测试，以成为首个被批准用于ALI/ARDS的有效药物疗法，并满足这一巨大的未得到满足的医疗需求。

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. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to evaluate the clinical utility of a novel anti-tissue factor monoclonal antibody, ALT-836, for treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in a 90-patient, randomized, placebo-controlled, double-blind, multi-center Phase 2 clinical study using a multi-dose regimen. If this trial successfully achieves its clinical efficacy endpoints, ALT-836 will then be tested in a pivotal Phase 3 registration trial needed for regulatory approval in order to become the first effective pharmaceutical treatment approved for ALI/ARDS and address this large unmet medical need.