Expanding the Market and Success Rates for Myeloablative Cancer Treatments Using PUL-042, an Innate Immune Stimulant

Pulmotect，Inc.成立于2007年，目的是将诱导肺部天然免疫抵抗的发现转化为 转化为治疗方法，提供对吸入病原体的保护。我们的技术平台是直接的结果 我们的创始人对肺上皮微生物耐药机制的基础研究。我们有 开发了一种吸入性治疗药物PUL-042，它可以立即预防广谱的 呼吸道病原体。PUL-042是一种临床期、特异性结合两种特性良好的合成物 分子，脂肽(Pam2CSK4)和寡脱氧核苷酸(ODN M362)，作为激动剂 Toll样受体TLR2/6和TLR9。这种独特的、专有的分子组合 协同作用，迅速而有力地刺激身体的自然防御能力。响应是本地化的，并且 特定于管理站点。雾化吸入PUL-042前后小鼠的治疗 结果提高了包括多种革兰氏阳性菌和革兰氏杆菌在内的病原体的存活率(其中三种 是A类生物恐怖物质)、真菌烟曲霉、仙台病毒和流感病毒。在每一个中 病例中，存活率的增加与肺部病原体负担的减少有关，而不是简单地增加 寄主对病原菌的耐性，这表明了一种抗性的作用机制。 Pulmotect的长期战略是利用其技术应对一系列来自 通过限制病原体负担和疾病传播来吸入病原体。适用范围： PUL-042目前正在开发中，包括用于免疫抑制患者、大流行性流感、哮喘 与病毒感染和人为生物恐怖威胁以及自然出现的威胁有关的恶化 病毒。虽然这种广谱技术没有被设想为取代传统的疫苗方法，但其 价值和差异化在于能够提供不受限制的即时基于主机的保护 病原体的身份。这项提案范围之外的潜在迹象是协同作用的， 建立在我们在这一领域最早研究以来建立的实验方法上。科学的 增强肺部天然免疫系统的基础正在迅速扩大，因为我们更好地了解了 潜在的作用机制。 这项提议的主要目标是完成免疫抑制癌症患者的第二阶段临床试验。 这将是一项多中心随机双盲试验，将PUL-042与安慰剂进行比较 肺炎的总体发病率和严重程度，特别是那些已被筛查为 入学前感染副流感。试验的三个目标如下所述。 ·主要目的：确定PUL-042吸入液在慢性阻塞性肺疾病患者中的安全性和耐受性 有记录的副流感感染。 ·次要目标：确定PUL-042雾化溶液预防慢性前列腺癌进展的疗效 记录的副流感感染到临床记录的下呼吸道感染。 ·探索目标：1)评估PUL-042对副流感病毒滴度和中和的影响 2)评价PUL-042对小鼠鼻冲洗液中微生物群和病毒体的影响 研究人群；以及3)确定PUL-042是否诱导针对PUL-042中和抗体 组件。 这些目标的成功实现将在MAN中证明概念验证，并进一步验证 市场使用的技术。在有保障的匹配资金已经到位的情况下，NIH的这项提案旨在 帮助将项目推向最终目标，而不是提供启动过程的初始种子资金。这个 公司将处于有利地位，能够推进现有的协作、伙伴关系和讨论 领先的大型制药和生物技术组织，加快进入市场的道路，以解决 许多患者目前面临的严重未得到满足的需求。

Pulmotect, Inc. was founded in 2007 to translate discoveries that induce innate immune resistance in the lung into therapeutics that will provide protection from inhaled pathogens. Our technology platform is a direct result of basic research by our founders on the mechanisms of microbial resistance in the lung epithelium. We have developed an inhaled therapeutic, PUL-042, that provides immediate protection against a broad spectrum of respiratory pathogens. PUL-042 is a clinical stage, specific combination of two well-characterized synthetic molecules, a lipopeptide (Pam2CSK4) and an oligodeoxynucleotide (ODN M362) that act as agonists of the Toll-like Receptors TLR2/6 and TLR9, respectively. This unique, proprietary combination of molecules synergizes to rapidly and powerfully stimulate the body’s natural defenses. The response is localized and specific to the site of administration. In mice, treatment before and after exposure with aerosolized PUL-042 results in increased survival rates to pathogens including multiple Gram+ and Gram– bacteria (three of which are Class A bioterror agents), the fungus Aspergillus fumigatus, and the Sendai and influenza viruses. In each case, increased survival is associated with a reduction of lung pathogen burden, not simply increased tolerance to the pathogen by the host, which indicates a resistance mechanism of action. Pulmotect's long-term strategy is to leverage its technology across a wide array of important threats from inhaled pathogens by limiting the pathogen burden and transmission of disease. The range of applications for PUL-042 currently in development includes use in immunosuppressed patients, pandemic influenza, asthma exacerbations associated with viral infections and manmade bioterror threats as well as naturally emerging viruses. While this broad spectrum technology is not envisioned to replace traditional vaccine approaches, its value and differentiation reside in the ability to confer immediate host-based protection that is not limited by the identity of the pathogen. The potential indications that lie outside the scope of this proposal are synergistic, building on experimental methods that we established since our earliest research in this field. The scientific basis of boosting the innate immune system in the lungs is rapidly expanding as we better understand the underlying mechanism of action. The primary goal of this proposal is to complete a Phase II clinical trial in immunosuppressed cancer patients. This will be a multi-center randomized double-blind trial that will compare PUL-042 against placebo on the overall incidence and severity of pneumonia, specifically on those who have been screened to have a parainfluenza infection prior to enrollment. The three objectives of the trial are described below. • Primary objective: to determine the safety and tolerability of PUL-042 inhalation solution in patients with documented parainfluenza infection. • Secondary objective: to determine the efficacy of PUL-042 inhalation solution to prevent the progression of documented parainfluenza infection to clinically documented lower respiratory tract infection. • Exploratory objectives: 1) evaluate the effect of PUL-042 on parainfluenza viral titers and neutralizing antibodies; 2) evaluate the effect of PUL-042 over time on the microbiome and virome in nasal washes in the study population; and 3) determine whether PUL-042 induces neutralizing antibodies against PUL-042 components. The successful achievement of these objectives will demonstrate proof-of-concept in man and further validate the technology for market use. With secured matching funds already in place, this NIH proposal is designed to help move the project to the end goal, rather than provide the initial seed funds to start the process. The Company would be well positioned to advance existing collaborations, partnerships and discussions with leading large pharma and biotechnology organizations, accelerating the path to the market to address the serious unmet needs that many patients are currently facing.