A Novel Glycosaminoglycan-Based Therapeutic for Chronic Rhinosinusitis

项目总结 慢性鼻-鼻窦炎(CRS)是美国最常见的炎症性疾病之一，影响多达 12%的人口，并大大降低了患者的生活质量和生产力。在四年时间里， 美国每年用于治疗CRS患者的医疗支出从90亿美元增加到640亿美元，其中 外科治疗失败的患者中有20%的患者的外科治疗相应增加 防线-生理盐水鼻腔冲洗和皮质类固醇鼻腔喷雾。新近批准的或新兴的 CRS的技术继续依赖于皮质类固醇治疗和新的给药方法。然而，安全 对长期使用皮质类固醇的担忧仍然存在，最终结果仍然不够。 疾病的控制。GlycoMira Treateutics公司的GM-1111是一种基于糖胺聚糖的合成药物 靶向先天免疫分子Toll样受体2和4以减少下游的候选 炎症后果，如炎性细胞因子的产生和炎性物质的流入 免疫细胞进入受损组织。在CRS模型中，鼻腔给药GM-1111胜过竞争对手 皮质类固醇作为一种有效的治疗方法来减轻鼻窦炎症，显著降低了 炎性细胞因子的产生、白细胞的渗透、粘液堆积和鼻气鼻腔上皮细胞 屏障破坏/粘液纤毛清除受损。研究还表明，GM-1111是 安全和稳定时，以广泛的配方和剂量给药。在这份IIB阶段提案中，通用汽车- 1111将被进一步开发为有效治疗CRS的新疗法。总体目标是 将GM-1111推进到研究性新药(IND)申请和人体临床试验，这将 通过在两个动物物种(AIM)中完成启用IND的安全/毒理学研究来实现 1)、用于临床试验的GM-1111药品稳定性试验和IND申请提交(目标2)。

PROJECT SUMMARY Chronic rhinosinusitis (CRS) is one of the most prevalent inflammatory diseases in the U.S., affecting up to 12% of the population and substantially diminishing the quality of life and productivity of patients. In four years, the annual U.S. health care expenditure to treat patients with CRS increased from $9B to $64B, with a corresponding rise in surgical treatment for those 20% of patients who fail medical management with the first line of defense – saline nasal irrigation and corticosteroid nasal sprays. Recently approved or emerging technologies for CRS continue to rely on corticosteroid treatment with new delivery methods. However, safety concerns over the long-term use of corticosteroids still remain, and the end result continues to be inadequate control of the disease. GlycoMira Therapeutics’ GM-1111 is a synthetic glycosaminoglycan-based drug candidate that targets innate immunity molecules Toll-like receptor 2 and 4 to reduce downstream inflammatory consequences, such as the production of inflammatory cytokines and influx of inflammatory immune cells into damaged tissues. In models of CRS, intra-nasal administration of GM-1111 outcompetes corticosteroids as an effective treatment for reducing sinonasal inflammation, with significantly decreased inflammatory cytokine production, leukocyte infiltration, mucus accumulation, and air-sinonasal epithelial cell barrier breakdown/impaired mucociliary clearance. Studies have additionally demonstrated that GM-1111 is safe and stable when administered in a wide range of formulations and doses. In this Phase IIB proposal, GM- 1111 will be further developed as a new therapeutic for the effective treatment of CRS. The overall goal is to advance GM-1111 to an Investigational New Drug (IND) application filing and human clinical trials, which will be accomplished through the completion of IND-enabling safety/toxicology studies in two animal species (Aim 1), GM-1111 drug product stability testing for clinical trial use, and IND application submission (Aim 2).