Phase II Clinical Trial of Lactoferrin in Asthma

乳铁蛋白治疗哮喘的 II 期临床试验

• 批准号: 6934979
• 负责人: ATUL VARADHACHARY
• 金额: $ 74.99万
• 依托单位: AGENNIX, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6934979
• 关键词: asthma; clinical research; clinical trial phase II; drug administration rate /duration; drug screening /evaluation; human subject; human therapy evaluation; lactoferrin; oral administration; patient oriented research; pharmacokinetics; recombinant proteins; respiratory disorder chemotherapy; respiratory pharmacology; sign /symptom

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

描述（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的 II 期临床试验中的疗效。 哮喘是美国最流行的慢性炎症疾病之一，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、发病率和死亡率仍在持续增加，并且对能够更有效和安全地治疗这种疾病的新型口服药物的医疗需求仍然存在巨大的未满足的医疗需求。 乳铁蛋白是一种多功能免疫调节蛋白，存在于血清和外分泌分泌物（例如牛奶和初乳）中，作为主要宿主防御系统的组成部分。它也是中性粒细胞次级颗粒的成分，并在炎症部位局部释放。 RhLF 是该蛋​​白质的重组版本，在所有物质方面均与天然蛋白质相同，仅其糖基化性质不同。医药级rhLF可以大规模生产（每年数吨产品）。 我们已经证明，口服 rhLF 可以防止绵羊和灵长类哮喘模型的气道影响和炎症浸润。在过敏性哮喘绵羊模型中，口服 rhLF 可以分别抑制早期和晚期哮喘反应以及气道超敏反应高达 77%、90% 和 100%。这些结果与 ZileutonTM 和孟鲁司特钠 (Singulair(tm)) 等领先批准药物在相同临床前模型中获得的结果相当或优于这些结果。在本次 SBIR 资助的第一阶段中，先前在绵羊中观察到的 rhLF 的抗哮喘活性在食蟹猴（一种非人类灵长类哮喘模型）中得到了证实。灵长类动物研究还帮助我们确定了 2 期试验的适当临床剂量。这项工作的详细信息在本申请随附的第一阶段报告中提供。 RhLF 的抗哮喘活性似乎是通过一种新机制发挥作用的。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 TH2 向 TH1 转变，有助于减少与哮喘相关的炎症。在动物研究和人体试验中，口服 rhLF 也被证明是安全的且耐受性良好。在一项为期 6 个月的猴子安全毒性研究中，小鼠和猴子服用 RhLF 的剂量高达 1000 毫克/公斤，持续时间长达 183 天。在治疗阶段、实验室测试或组织病理学中未发现与药物相关的不良事件。在人类中，24 小时内 rhLF 的给药剂量高达 15 克，持续一段时间内每天的给药剂量高达 9 克。已对 211 人进行口服 rhLF 治疗，未发生任何与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 的强大安全性和易于给药，rhLF 可能代表一种令人兴奋的、安全的新型哮喘疗法。因此，我们请求支持进行 2 期人体临床试验，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功效。我们将对 30 名轻度至中度哮喘患者进行为期 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（通过标准参数（包括 FEV1、哮喘症状评分和吸入 β2- 的使用）进行测量）激动剂救援药物。患者登记和评估将由独立临床医生在主要学术机构独立进行