A Disease-Modifying Protein Therapeutic for the Treatment of COPD

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.