A Novel Glycosaminoglycan-Based Therapeutic for Chronic Rhinosinusitis

项目摘要 慢性鼻窦炎（CRS）是美国最常见的炎症性疾病之一，影响多达 占人口的12%，大大降低了患者的生活质量和生产力。四年来， 美国每年用于治疗CRS患者的医疗保健支出从90亿美元增加到640亿美元， 对于那些第一次医疗管理失败的20%的患者， 防线盐水鼻腔冲洗和皮质类固醇鼻腔喷雾剂。最近批准或出现 用于CRS的技术继续依赖于具有新的递送方法的皮质类固醇治疗。然而，安全 对长期使用皮质类固醇的担忧仍然存在，最终结果仍然不充分 控制疾病。GlycoMira Therapeutics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的候选物，以减少下游 炎性后果，如炎性细胞因子的产生和炎性细胞因子的流入， 免疫细胞进入受损组织。在CRS模型中，GM-1111鼻内给药优于 皮质类固醇作为减少鼻窦炎症的有效治疗， 炎性细胞因子产生、白细胞浸润、粘液积聚和鼻窦上皮细胞 屏障破坏/粘膜纤毛清除受损。研究还表明，GM-1111是 当以广泛的制剂和剂量给药时安全且稳定。在这份IIB阶段提案中，GM- 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， 通过在两种动物种属中完成IND使能安全性/毒理学研究（Aim 1）、临床试验用GM-1111制剂稳定性试验和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).