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

基本信息

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
项目类别：
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

项目摘要

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 万美国人每周消耗对乙酰氨基酚 (APAP)。不幸的是，过量服用 APAP 会导致肝毒性，并导致一半以上的急性在美国的肝衰竭病例中，N-乙酰半胱氨酸是 APAP 过量的唯一解毒剂。摄入 APAP 后 10 小时内服用有效，但许多患者并不主动寻求。 N-乙酰胱氨酸治疗窗口期间的治疗目前，肝移植是最有效的治疗方法。这些晚期患者唯一可用的治疗选择是 APAP 毒性。用于美国和世界各地的肝移植。该SBIR二期项目的目标是开发一种抗炎合成硫酸乙酰肝素寡糖，GLY-202，用于 APAP 过量患者，特别是晚期 GLY- 患者。 202是在化合物优化研究之后被选择的，目的是为了找出更小、更容易的在 APAP 过量模型中，与 18 聚体相比，合成具有体内功效的寡糖。与 18-mer 不同，GLY-202 的合成可以通过更短的合成路线实现，大大降低了生产成本并减少了重大的商业化障碍。该 II 期阶段将重点关注 IND 启用研究，包括 GLY-202 原料药化学、制造和控制 (CMC) 活动（目标 1）、药理学（目标 2）和毒性研究（目标 3）的执行将展示综合的可扩展性和中试生产规模的可重复性以及药理学和毒性的功效和安全性在第二阶段研究期间，Glycan Therapeutics 将提交孤儿药资格认定。申请孤儿药资格的好处包括通过费用获得的重大经济利益。此外，临床试验招募将得到豁免和税收抵免。较小，意味着可以充分制备所需的GLY-202量在 IIb 期研究中，我们将完成 GMP 生产，制定、提交IND申请并进行1期临床试验该项目取得成功。将提供一种通过靶向 HMGB1 介导的治疗药物引起的肝毒性的新方法使用一流的治疗方法治疗炎症。