A Disease-Modifying Protein Therapeutic for the Treatment of COPD

项目总结 慢性阻塞性肺疾病(COPD)是全球第三大死亡原因，为323万人 (2019年)，而近4亿人受到影响。慢性阻塞性肺疾病是一种异质性、多表型的肺部疾病。 吸烟、蒸发、烹饪、森林火灾、污染、化学品暴露和许多 职业危害(例如，第一反应人员、军事、农业和工业工人)。最常见的形式 慢性阻塞性肺病的主要病因是慢性支气管炎，慢性支气管炎与粘液过度分泌有关，导致粘液分泌显著减少。 肺功能降低导致生活质量下降。 目前治疗慢性阻塞性肺疾病的方法主要是治疗症状，而不是有意义地改变病程。 目前还没有针对COPD患者的真正改善疾病的治疗方法。不同的家庭 许多蛋白水解酶与慢性阻塞性肺疾病有关。最近，一种特定的蛋白水解酶被证明上调。 在肺上皮细胞和巨噬细胞中，其表达与疾病的严重程度直接相关。 在人类COPD患者中。靶标是一种多功能的膜结合蛋白，负责处理细胞因子、生长 细胞表面的因子、受体和受体配体。Verra Treateutics已经开发出一种可溶性蛋白质 抑制剂VTH245，选择性地抑制蛋白水解酶活性并阻断有害活动 慢性阻塞性肺疾病（慢阻肺）。这种创新的蛋白质抑制剂在特异性方面具有显著的优势(与小分子相比 抑制物)、渗透性(小于单抗)和免疫原性(基于天然的 发生的蛋白质序列)。在我们的第一阶段项目中产生的数据表明，VTH2 45处理 在吸烟诱导COPD的金标准小鼠模型中，1)显著降低了肺组织的生物标志物 炎症和破坏；2)肺灌洗液中的炎性细胞数量减少到接近空气的水平；以及3) 粘液高分泌减少。此外，这些结果符合或超过了市场上销售的药物的表现， 罗氟司特。虽然罗氟司特治疗通常与限制其使用的一系列毒性有关，但VTH2 45 耐受性好，6个月以上存活率最高(20/20只)。此第二阶段SBIR Project将扩展我们在第一阶段的发现，并提供关键的启用IND的安全数据，以告知未来的First in-in- 通过执行下列具体目标进行人体研究：目标1：确定 VTH_245治疗慢性阻塞性肺疾病的疗效比较 皮下和吸入给药途径，确定用于AIM毒性研究的单一途径 目标2：为VTH2 45工艺开发执行关键的CMC活动并产生高质量 VT245，用于目标3中的毒性评估；以及目标3：生成VTH2 45的初步安全概况 以支持IND审批。第二阶段计划的成功完成将进一步确定目标产品 VTH2 45的简介，并为IND提交以支持临床开发计划提供关键数据。

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.