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

使用先天免疫兴奋剂 PUL-042 扩大清髓性癌症治疗的市场和成功率

• 批准号: 9061821
• 负责人: Brenton Scott
• 金额: $ 99.88万
• 依托单位: PULMOTECT, INC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9061821
• 关键词: Achievement; Address; Agonist; Agreement; Aspergillus fumigatus; Asthma; Bacteria; Basic Science; Biotechnology; Breathing; Cancer Patient; Clinical; Clinical Research; Clinical Trials; Collaborations; Communicable Diseases; Cyclic GMP; Data; Development; Dose; Double-blind trial; Enrollment; Epithelium; Evaluation; Funding; Goals; Hematologic Neoplasms; Hematology; Human; Immune; Immune system; Immunity; Immunocompromised Host; Incidence; Infection; Lead; Lower Respiratory Tract Infection; Lung; Marketing; Methods; Mus; Myeloablative Chemotherapy; Nasal Lavage Fluid; Parainfluenza; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Placebos; Pneumonia; Positioning Attribute; Prevention; Process; Pulmonology; Randomized; Recruitment Activity; Research; Resistance; Safety; Secure; Seeds; Sendai virus; Severities; Site; Staging; Survival Rate; TLR2 gene; Technology; Testing; Therapeutic; Time; Toll-like receptors; Translating; United States National Institutes of Health; University of Texas M D Anderson Cancer Center; Vaccines; Viral; Virus; Virus Diseases; aerosolized; base; cancer therapy; clinical research site; design; disease transmission; follow-up; fungus; healthy volunteer; immune resistance; immunosuppressed; individual patient; influenzavirus; man; microbial; microbiome; neutralizing antibody; novel therapeutics; oncology; outreach; pandemic influenza; pathogen; phase I trial; phase II trial; prevent; resistance mechanism; respiratory; response; study population; success; technology development; virome

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.

Pulmotect, Inc. 成立于 2007 年，致力于转化诱导肺部先天免疫抵抗的发现 进入可提供针对吸入病原体的保护的治疗方法。我们的技术平台是直接结果 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 开发了一种吸入疗法 PUL-042，可针对多种疾病提供立即保护 呼吸道病原体。 PUL-042是一种临床阶段的、两种特征良好的合成药物的特定组合 分子，脂肽（Pam2CSK4）和寡脱氧核苷酸（ODN M362）作为激动剂 Toll 样受体分别为 TLR2/6 和 TLR9。这种独特的、专有的分子组合 协同作用，快速有力地刺激身体的自然防御能力。响应是本地化的并且 具体到给药部位。在小鼠中，暴露于雾化 PUL-042 之前和之后的治疗 导致病原体的存活率提高，包括多种革兰氏+和革兰氏-细菌（其中三种 是 A 级生物恐怖制剂）、真菌烟曲霉、仙台病毒和流感病毒。在每个 在这种情况下，生存率的提高与肺部病原体负担的减少有关，而不仅仅是增加 宿主对病原体的耐受性，表明存在抵抗作用机制。 Pulmotect 的长期战略是利用其技术应对来自以下领域的各种重要威胁： 通过限制病原体负担和疾病传播来吸入病原体。应用范围 目前正在开发的 PUL-042 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相关的恶化 病毒。虽然这种广谱技术预计不会取代传统的疫苗方法，但它 价值和差异化在于能够立即提供基于主机的保护，而不受 病原体的身份。本提案范围之外的潜在迹象具有协同作用， 建立在我们自该领域最早研究以来建立的实验方法的基础上。科学的 随着我们更好地了解，增强肺部先天免疫系统的基础正在迅速扩大 潜在的作用机制。 该提案的主要目标是在免疫抑制的癌症患者中完成 II 期临床试验。 这将是一项多中心随机双盲试验，将比较 PUL-042 与安慰剂的疗效 肺炎的总体发病率和严重程度，特别是那些经过筛查的人 入组前有副流感感染。该试验的三个目标如下所述。 • 主要目标：确定 PUL-042 吸入溶液在患有以下疾病的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 吸入溶液预防病情进展的功效 记录的副流感感染到临床记录的下呼吸道感染。 • 探索性目标：1) 评估 PUL-042 对副流感病毒滴度和中和的影响 抗体； 2) 评估 PUL-042 随着时间的推移对鼻洗液中微生物组和病毒组的影响 研究人群； 3) 确定 PUL-042 是否诱导针对 PUL-042 的中和抗体 成分。 这些目标的成功实现将在人类中展示概念验证并进一步验证 市场使用的技术。随着有保障的配套资金已经到位，这项 NIH 提案旨在 帮助项目实现最终目标，而不是提供初始种子资金来启动该过程。这 公司将有能力推进现有的合作、伙伴关系和讨论 领先的大型制药和生物技术组织，加速进入市场的道路，以解决 许多患者目前面临着严重的未满足的需求。