A Disease-Modifying Protein Therapeutic for the Treatment of COPD

项目摘要 慢性阻塞性肺疾病（COPD）是全球第三大死亡原因，有323万人 （2019年），而近4亿人受到其影响。COPD是一种异质性、多表型疾病， 来自吸烟，vaping，烹饪，森林火灾，污染，化学品暴露以及许多 职业危害（例如，第一反应，军事，农业和工业工人）。最常见的形式 慢性支气管炎是慢性支气管炎，它与粘液分泌过多有关，导致肺功能大大降低。 导致生活质量下降的肺功能。 目前对COPD的治疗主要是治疗症状，而没有有意义地改变疾病的进程。 目前还没有真正的疾病改善治疗可用于COPD患者。不同家庭 与COPD有关。最近，一种特定的蛋白酶被证明是上调 在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COPD患者中。靶点是一种多效性膜结合蛋白， 细胞表面的因子、受体和受体配体。Verra Therapeutics开发了一种可溶性蛋白质 抑制剂，VTH 245，其选择性地抑制蛋白水解活性并阻断有害活性， 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（基于天然的 发生蛋白质序列）。在我们的第一阶段项目中产生的数据表明，VTH 245治疗 在香烟烟雾诱导的COPD的金标准小鼠模型中，1）显著降低肺的生物标志物， 炎症和破坏; 2）将肺灌洗液中的炎性细胞计数降低至接近空气的水平;以及3） 减少粘液分泌过多。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相关，但VTH 245 耐受性良好，并在6个月内显示出最高的存活率（20/20只动物）。第二阶段SBIR 该项目将扩展我们第一阶段的研究结果，并提供关键的IND支持安全性数据，为未来的首次临床试验提供信息。 通过执行以下具体目标进行人体研究：目标1：确定 通过比较两种临床相关的VTH 245给药提供的功效， 皮下和吸入给药途径，确定用于Aim毒性研究的单一途径 3;目标2：执行VTH 245工艺开发的关键CMC活动，并产生高质量 用于目标3中毒性评价的VT 245;和目标3：生成VT 245的初步安全性特征 支持IND批准。第二阶段计划的成功完成将进一步确定目标产品 VTH 245的特征，并为IND提交提供关键数据，以支持临床开发计划。

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.