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A Novel Glycosaminoglycan-Based Therapeutic for Chronic Rhinosinusitis

一种基于糖胺聚糖的慢性鼻窦炎治疗方法

基本信息

批准号：
10437945
负责人：
Justin Rodney Savage
金额：
$ 97.6万
依托单位：
GLYCOMIRA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10437945
关键词：
Adrenal Cortex Hormones Adverse effects Affect Air Animals Anti-Inflammatory Agents Barium Benzalkonium Chloride Biological Assay Biological Products Blood specimen Canis familiaris Cardiovascular system Cells Clinical Trials Complex Data Disease Dose Drug Costs Drug or chemical Tissue Distribution Emerging Technologies Engineering Ensure Epithelial Cells Etiology Exhibits Formulation Genetic Transcription Glycosaminoglycans Goals Guidelines Health Expenditures Heparin Human Immune Impaired cognition Impairment Infiltration Inflammation Inflammation Mediators Inflammatory Injectable Innate Immune Response Intranasal Administration Investigational Drugs Investigational New Drug Application Irrigation Laboratories Lead Leukocytes Measures Mediating Medical Mental Depression Methods Micronucleus Tests Modeling Molecular Weight Monoclonal Antibodies Mucociliary Clearance Mucolytics Mucous body substance Nasal Polyps Natural Immunity Nose Operative Surgical Procedures Outcome Paranasal Sinus Diseases Pathogenesis Patient-Focused Outcomes Patients Pattern recognition receptor Peptide Hydrolases Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Population Prevalence Production Productivity Property Quality of life Rattus Recovery Regulation Reporting Rivers Route Running Safety Saline Sampling Signal Transduction Sinus Sinusitis Sleep Disorders Sprague-Dawley Rats Sputum Steroids Sulfate Symptoms TLR2 gene Technology Telemetry Temperature Testing Therapeutic Time Tissues Topical application Toxicokinetics Toxicology Treatment Cost analytical method aqueous base chronic rhinosinusitis clinical development cost cytokine disorder control drug candidate drug distribution effective therapy experience flexibility improved in vivo lead candidate light scattering method development neurobehavior novel novel therapeutics pre-clinical respiratory safety study seal stability testing therapeutically effective

项目摘要

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).

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）。