A Disease-Modifying Protein Therapeutic for the Treatment of COPD

用于治疗慢性阻塞性肺病的疾病修饰蛋白疗法

• 批准号: 10602047
• 负责人: Christopher Lucas Prince
• 金额: $ 136.45万
• 依托单位: VERRA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602047
• 关键词: Aerosols; Agricultural Workers; Agriculture; Air; Amino Acid Sequence; Animals; Binding; Binding Proteins; Biological Assay; Biological Availability; Biological Markers; Biology; Bronchoalveolar Lavage; Cause of Death; Cell Count; Cell Line; Cell surface; Cells; Chemical Exposure; Chronic Bronchitis; Chronic Obstructive Pulmonary Disease; Clinical; Data; Desmosine; Development; Disease; Disease model; Disintegrins; Dose; Epithelial Cells; Evaluation; Family; Fermentation; Fire - disasters; Future; Growth Factor; Healthcare; Human; In Vitro; Industrialization; Infiltration; Inflammatory; Inhalation; Intake; Ligands; Lung; Macrophage; Maximum Tolerated Dose; Membrane; Metalloproteases; Military Personnel; Modeling; Monoclonal Antibodies; Mucous body substance; Nontypable Haemophilus influenza; Oropharyngeal; Outcome; Particle Size; Pathologic Processes; Patients; Penetration; Peptide Hydrolases; Performance; Persons; Pharmaceutical Preparations; Phase; Pollution; Process; Production; Program Development; Proteins; Pulmonary Inflammation; Quality of life; Rattus; Retina; Risk; Route; Safety; Severity of illness; Small Business Innovation Research Grant; Smoke; Smoking; Specificity; Survival Rate; T cell response; Therapeutic; Tissues; Toxic effect; Validation; Work; aerosolized; alveolar epithelium; analytical method; arm; aspirate; associated symptom; cigarette smoke-induced COPD; clinical development; clinically relevant; comparative efficacy; cooking; cost effective; cytokine; disease phenotype; drug market; first-in-human; forest; immunogenicity; improved outcome; in vivo; indexing; inhibitor; innovation; lung injury; manufacture; member; method development; mouse model; mucus hypersecretion; novel; occupational hazard; pharmacologic; phase 1 study; programs; pulmonary function; receptor; small molecule inhibitor; subcutaneous; symptom treatment; therapeutic protein; vaping

PROJECT SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death worldwide at 3.23 million (2019), while nearly 400 million suffer its effects. COPD is a heterogeneous, multi-phenotypic disease with lung damage derived from smoking, vaping, cooking, forest fires, pollution, chemical exposure, and numerous occupational hazards (e.g., 1st responders, military, agricultural and industrial workers). The most common form of COPD is chronic bronchitis, which is associated with mucus hypersecretion that results in greatly reduced lung function leading to a decreased quality of life. Current treatments for COPD largely treat symptoms without meaningfully altering the course of the disease. There are currently no truly disease-modifying treatments available for COPD patients. Different families of proteases have been implicated in COPD. Recently, a specific protease has been shown to be upregulated in lung epithelial cells and macrophages, and its expression in these cells correlates directly with disease severity in human COPD patients. The target is a pleiotropic membrane bound protein that processes cytokines, growth factors, receptors, and receptor ligands on the cell surface. Verra Therapeutics has developed a soluble protein inhibitor, VTH245, that selectively inhibits the proteolytic activity and blocks deleterious activities in models of COPD. This innovative protein inhibitor has significant advantages in specificity (compared to small molecule inhibitors), penetration (smaller than monoclonal antibodies), and immunogenicity (based on a naturally occurring protein sequence). Data generated in our Phase I project have demonstrated that VTH245 treatment in a gold-standard mouse model of cigarette smoke-induced COPD 1) significantly reduced biomarkers of lung inflammation and destruction; 2) reduced inflammatory cell counts in the lung lavage to near-air levels; and 3) reduced mucus hypersecretion. Further, these results matched or exceeded performance of the marketed drug, roflumilast. While roflumilast treatment is commonly associated with a range of toxicities that limit its use, VTH245 was well tolerated and displayed the highest survival rate over 6-months (20/20 animals). This Phase II SBIR project will extend our findings from Phase I and provide key IND-enabling safety data to inform future first-in- human studies through the execution of the following Specific Aims: Aim 1: To identify the preferred route of administration for VTH245 for treating COPD by comparing the efficacy provided by two clinically relevant routes of administration, subcutaneous and inhaled, determining a single route for use in toxicity studies in Aim 3; Aim 2: To perform critical CMC activities for VTH245 process development and generate high quality VT245 for use in toxicity evaluations in Aim 3; and Aim 3: To generate a preliminary safety profile of VTH245 to support IND approval. Successful completion of the Phase II program will further define the target product profile for VTH245 and provide critical data for an IND submission to support a clinical development program.

项目概要 慢性阻塞性肺疾病 (COPD) 是全球第三大死亡原因，共有 323 万人死亡 （2019），而近 4 亿人受到其影响。 COPD 是一种异质性、多表型的肺部疾病 吸烟、电子烟、烹饪、森林火灾、污染、化学品暴露等造成的损害 职业危害（例如第一响应人员、军人、农业和工业工人）。最常见的形式 COPD 的病因是慢性支气管炎，它与粘液分泌过多有关，导致粘液分泌量大大减少 肺功能下降导致生活质量下降。 目前对慢性阻塞性肺病的治疗主要是治疗症状，而没有有意义地改变病程。 目前尚无真正可用于慢性阻塞性肺病患者的疾病缓解治疗方法。不同的家庭 蛋白酶与慢性阻塞性肺病有关。最近，一种特定的蛋白酶已被证明上调 存在于肺上皮细胞和巨噬细胞中，其在这些细胞中的表达与疾病严重程度直接相关 在人类慢性阻塞性肺病患者中。靶标是一种多效性膜结合蛋白，可处理细胞因子、生长 细胞表面的因子、受体和受体配体。 Verra Therapeutics 开发出一种可溶性蛋白质 抑制剂 VTH245，可选择性抑制蛋白水解活性并阻止模型中的有害活动 慢性阻塞性肺病。这种创新的蛋白质抑制剂在特异性方面具有显着的优势（与小分子相比） 抑制剂）、渗透性（小于单克隆抗体）和免疫原性（基于自然 发生的蛋白质序列）。我们的第一阶段项目中生成的数据表明，VTH245 治疗 在香烟烟雾诱发 COPD 的金标准小鼠模型中 1) 显着降低了肺部生物标志物 炎症和破坏； 2）将肺灌洗液中的炎症细胞计数减少至接近空气水平；和 3) 减少粘液过度分泌。此外，这些结果匹配或超过了上市药物的性能， 罗氟司特。虽然罗氟司特治疗通常与一系列限制其使用的毒性有关，但 VTH245 耐受性良好，并且在 6 个月内表现出最高的存活率（20/20 动物）。本次 SBIR 第二阶段 该项目将扩展我们第一阶段的研究结果，并提供关键的 IND 支持安全数据，为未来的首创提供信息 通过执行以下具体目标进行人体研究： 目标 1：确定首选途径 通过比较两种临床相关药物提供的功效，给予 VTH245 治疗 COPD 给药途径，皮下和吸入，确定 Aim 毒性研究中使用的单一途径 3；目标 2：执行 VTH245 工艺开发的关键 CMC 活动并产生高质量 VT245 用于目标 3 中的毒性评估；目标 3：生成 VTH245 的初步安全概况 支持 IND 批准。二期计划的成功完成将进一步明确目标产品 VTH245 的概况，并为 IND 提交提供关键数据，以支持临床开发计划。