Development of heparan sulfate-based therapeutics to treat inflammatory diseases

开发基于硫酸乙酰肝素的炎症性疾病疗法

• 批准号: 10820685
• 负责人: Zhangjie Wang
• 金额: $ 87.43万
• 依托单位: GLYCAN THERAPEUTICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-14 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10820685
• 关键词: Acetaminophen; Acute; Acute Liver Failure; Address; Adverse effects; American; Anti-Inflammatory Agents; Antidotes; Award; Biological Assay; Biological Process; Chemicals; Clinical; Clinical Trials Design; Complex Mixtures; Consumption; Cysteine; Cystine; Development; Disease; Dose; Drug Kinetics; Fees; Formulation; Goals; Good Manufacturing Process; HMGB1 gene; Heparin; Heparitin Sulfate; Hepatotoxicity; Hour; Immune response; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Injury; Isotope Labeling; Label; Licensing; Liver Failure; Liver Regeneration; Mediating; Methods; Miniature Swine; Modeling; Natural Source; North Carolina; Oligosaccharides; Orphan Drugs; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase; Phase I Clinical Trials; Polysaccharides; Preparation; Production; Protocols documentation; Publishing; Quality Control; Rattus; Regimen; Reporting; Reproducibility; Route; Safety; Scheme; Sepsis; Small Business Innovation Research Grant; Sulfate; Taxes; Therapeutic; Therapeutic Effect; Toxic effect; Toxicokinetics; Translational Research; Trauma; Universities; acetaminophen overdose; chemical synthesis; clinical trial recruitment; commercialization; comparative; comparative efficacy; cost; design; drug discovery; drug induced liver injury; heparin-induced thrombocytopenia; hepatoprotective; immunogenicity; in vivo; lead candidate; liver injury; liver transplantation; manufacture; mouse model; novel strategies; novel therapeutics; pharmacokinetics and pharmacodynamics; phase 1 study; phase 2 study; pre-Investigational New Drug meeting; receptor for advanced glycation endproducts; subcutaneous; success; sugar; systemic inflammatory response; therapeutic target; translational medicine; waiver

Abstract More than 60 million Americans consume acetaminophen (APAP) on a weekly basis. Unfortunately, an overdose of APAP causes liver toxicity and is responsible for over half of acute liver failure cases in the US. N-acetyl cysteine is the only antidote for APAP overdose and is effective if given within 10 hours after APAP ingestion. However, many patients don’t seek out treatment during the therapeutic window for N-acetyl cystine. Currently, a liver transplant is the only available treatment option for these late-presenting patients. APAP toxicity is a leading cause for liver transplantation in the US and worldwide. The goal of this SBIR phase II project is to develop an anti-inflammatory synthetic heparan sulfate oligosaccharide, GLY-202, for APAP overdose patients specifically late-presenting patients. GLY- 202 was selected after compound optimization studies in efforts to identify a smaller, easier to synthesize oligosaccharide with in vivo efficacy compared to 18-mer in the APAPoverdose model. Unlike 18-mer, the synthesis of GLY-202 can be achieved in a shorter synthetic route, substantially decreasing the production cost and reducing a significant commercialization barrier. This phase II period will focus on IND-enabling studies including GLY-202 drug substance chemical, manufacturing and control (CMC) activities (Aim 1), pharmacology (Aim 2) and toxicity studies (Aim 3). Execution of the proposed aims will demonstrate synthetic scalability and reproducibility in pilot production scale and efficacy and safety through pharmacology and toxicity studies. During the phase II period, Glycan Therapeutics will submit an Orphan Drug Designation application. Benefits of Orphan Drug status include significant financial benefits through fee waivers and tax credits for clinical expenses. Furthermore, the clinical trial recruitment will be comparatively small meaning that the amount of GLY-202 required can be sufficiently prepared by Glycan Therapeutics. In the phase IIb studies, we will complete GMP manufacturing, formulation, submit IND application and conduct Phase 1 clinical trials. The success of this project will provide a new approach to treat drug induced liver toxicity by targeting to HMGB1-mediated inflammation with a first-in-class therapeutic.

抽象的 超过6000万美国人每周消费对乙酰氨基酚（APAP）。 不幸的是，过量的APAP会导致肝脏毒性，并导致一半以上的急性 美国的肝衰竭病例。 N-乙酰基半胱氨酸是APAP过量的唯一解毒剂，IS 如果在APAP摄入后的10小时内给予有效。但是，许多患者没有寻找 N-乙酰基胱氨酸的治疗窗口中的治疗。目前，肝移植是 仅适用于这些晚期患者的可用治疗选择。 APAP毒性是主要原因 用于美国和全球的肝脏移植。 该SBIR II期项目的目标是开发抗炎合成乙酰肝素硫酸盐 寡糖，GLY-202，用于APAP过量患者，特别是晚期出现的患者。 g 在复合优化研究之后选择202，以识别较小，易于的 与磷灰岩模型中的18-mer相比，与体内效率合成的寡糖合成。 与18-mer不同，可以在较短的合成途径中实现Gly-202的合成， 大大降低了生产成本并降低了重大的商业化障碍。 这次II期时期将重点介绍包括GLY-202药物在内的辅助研究 化学，制造和控制（CMC）活动（AIM 1），药理学（AIM 2）和毒性 研究（目标3）。拟议的目标的执行将证明合成性可伸缩性和 通过药理学和毒性，试点生产规模以及安全性以及安全性的可重复性 研究。在第二阶段期间，聚糖治疗学将提交孤儿药 应用。孤儿毒品状况的好处包括通过费用的重大财务福利 临床费用的动力和税收抵免。此外，临床试验招募将是 相对较小的含义可以充分准备所需的GLY-202量 通过Glycan Therapeutics。在IIB期研究中，我们将完成GMP制造业， 编队，提交IND申请并进行第1阶段临床试验。这个项目的成功 将提供一种新的方法来治疗药物诱导的肝毒性，以靶向HMGB1介导 炎症采用一流的治疗。