Phase II Clinical Trial of Lactoferrin in Asthma

描述（由申请人提供）：本研究的目的是确定口服重组人乳铁蛋白（rhLF）在轻度至中度哮喘患者中的II期临床试验的疗效。 哮喘是美国最普遍的慢性炎症性疾病之一，影响约15%的人口。尽管在过去十年中对哮喘进行了深入的研究，但美国和发达国家的患病率、发病率和死亡率继续增加，并且对于可以更有效和安全地治疗这种疾病的新的口服给药药物仍然存在大量未满足的医疗需求。 乳铁蛋白是一种多功能的免疫调节蛋白，存在于血清和外分泌分泌物如乳汁和初乳中，在其中它作为主要宿主防御系统的组分。它也是中性粒细胞次级颗粒的组分，并在炎症部位局部释放。RhLF是蛋白质的重组形式，在所有物质方面与天然蛋白质相同，仅在其糖基化性质上不同。药用级rhLF可以大规模生产（每年生产吨产品）。 我们已经表明，口服rhLF保护对气道的影响和炎症浸润在绵羊和灵长类动物模型的哮喘。在绵羊过敏性哮喘模型中，口服rhLF对早期和晚期哮喘反应和气道超敏反应的抑制率分别高达77%、90%和100%。在相同的临床前模型中，这些结果与领先的获批药物（如齐留通TM和孟鲁司特钠（Singulair（tm）获得的结果相当或上级。在SBIR资助的I期研究中，先前在绵羊中观察到的rhLF的抗哮喘活性在Cynmolgus猴（一种非人灵长类哮喘模型）中得到证实。灵长类动物的工作也有助于为我们的2期试验确定适当的临床剂量。这项工作的细节载于本申请随附的第一阶段报告。 RhLF的抗哮喘活性似乎通过一种新的机制起作用。口服rhLF诱导肠道中关键细胞因子（包括IL-18）的产生，导致全身性TH 2向TH 1转变，有助于减少与哮喘相关的炎症。口服rhLF在动物研究和人体试验中也显示出安全性和良好的耐受性。在一项为期6个月的猴安全性-毒性研究中，已将RhLF以高达1000 mg/kg的剂量给予小鼠和猴长达183天。在治疗阶段、实验室检查或组织病理学检查中未观察到药物相关不良事件。在人类中，rhLF在24小时内以高达15 g的剂量给药，并在持续时间内以高达9 g/天的剂量给药。口服rhLF已口服给药211人没有单一药物相关的严重不良事件。 很少有口服有效的抗哮喘药物可供患者使用。鉴于口服rhLF的安全性和给药的方便性，rhLF可能代表一种令人兴奋的、安全的和新的哮喘治疗方法。因此，我们正在请求支持进行第二阶段人体临床试验，以评估口服rhLF对哮喘患者的疗效。 这项研究将寻求确定口服乳铁蛋白治疗轻度至中度哮喘症状的疗效。我们将在30例轻度至中度哮喘患者中进行一项为期28天的双盲、安慰剂对照临床试验，以评估乳铁蛋白缓解哮喘症状的有效性，这些症状通过标准参数（包括FEV、哮喘症状评分和吸入性β 2-激动剂急救药物的使用）进行测量。患者招募和评估将由独立临床医生在主要学术机构独立进行

DESCRIPTION (provided by applicant): The purpose of this research is to determine the efficacy of orally administered recombinant human lactoferrin (rhLF) in Phase II clinical trials in patients with mild to moderate asthma. Asthma is one of the most prevalent chronic inflammatory diseases in the United States affecting approximately 15 percent of the population. Despite intensive research on asthma over the past decade the prevalence, morbidity and mortality rates continue to increase in the U.S. and the developed world and there remains a large unmet medical need for new orally administered drugs that can more effectively and safely treat this disease. Lactoferrin is a multifunctional immunomodulatory protein found in serum and exocrine secretions such as milk and colostrum where it acts as a component of the primary host defense system. It is also a component of the neutrophil secondary granules and is released locally at the site of inflammation. RhLF, a recombinant version of the protein, is identical to the native protein in all material respects, differing only in the nature of its glycosylation. Pharmaceutical grade rhLF can be produced at large scale (tons of product per year). We have shown that oral rhLF protects against airway effects and inflammatory infiltration in both sheep and primate models of asthma. In the sheep model of allergic asthma, oral rhLF inhibited the early and late asthmatic responses and airway hypersensitivity by up to 77 percent, 90 percent and 100 percent, respectively. These results are comparable or superior to those obtained by leading approved drugs such as ZileutonTM and Montelukast Sodium (Singulair(tm)) in the same preclinical model. In Phase I of this SBIR grant, the anti-asthma activity of rhLF, previously observed in sheep, was confirmed in Cynmolgus monkeys, a non-human primate model of asthma. The primate work also helped identify an appropriate clinical dose for our Phase 2 trial. Details of this work are provided in the Phase I Report accompanying this application. RhLF's anti-asthma activity appears to act by a novel mechanism. Oral rhLF induces the production on key cytokines, including IL-18, in the gut resulting in a systemic TH2 to TH1 shift that helps reduce the inflammation associated with asthma. Oral rhLF has also shown to be safe and well tolerated in animal studies and in human trials. RhLF has been administered to mice and monkeys at doses as high as 1000 mg/kg and for up to 183 days in a 6-month monkey safety-toxicity study. No drug related adverse events were noted during the treatment phase, in laboratory tests or on histopathology. In humans, rhLF has been administered at a dose of up to 15 g in a 24 hour period and for up to 9 g/day for sustained periods of time. Oral rhLF has been administered orally to 211 people without a single drug related serious adverse event. Few orally administered effective anti-asthma drugs are available to patients. Given the robust safety profile and ease of administration of oral rhLF there exists a possibility that rhLF may represent an exciting, safe and novel therapy for asthma. Thus, we are requesting support to conduct a Phase 2 human clinical trial to evaluate the efficacy of oral rhLF in asthmatic patients. This research will seek to determine the efficacy of oral lactoferrin in treating the symptoms of mild to moderate asthma. We will conduct a 28 day double-blind, placebo-controlled clinical trial in 30 patients with mild to moderate asthma to assess the effectiveness of lactoferrin in relieving asthma symptoms as measured by standard parameters including FEV, asthma symptom scores and use of inhaled beta2-agonist rescue medications. Patient enrollment and evaluation will be conducted independently at major academic institutions by independent clinicians