Development of heparan sulfate-based therapeutics to treat inflammatory diseases

摘要 超过6000万美国人每周消耗对乙酰氨基酚（APAP）。 不幸的是，过量的APAP会导致肝毒性，并导致超过一半的急性 美国的肝衰竭病例。N-乙酰半胱氨酸是APAP过量的唯一解毒剂， 如果在服用APAP后10小时内给予，则有效。然而，许多患者并不寻求 在N-乙酰胱氨酸的治疗窗期间进行治疗。目前，肝移植是 这是这些迟发患者唯一可用的治疗选择。APAP毒性是导致 用于美国和世界各地的肝脏移植。 SBIR第二阶段项目的目标是开发一种抗炎的合成硫酸乙酰肝素 寡糖，GLY-202，用于APAP过量患者，特别是迟发患者。GLY- 202是在化合物优化研究后选择的，以确定一种更小、更容易 在APAP过量模型中，与18-mer相比，合成寡糖具有体内功效。 与18-mer不同，GLY-202的合成可以在更短的合成路线中实现， 大大降低了生产成本并降低了显著的商业化障碍。 该II期阶段将重点关注IND启动研究，包括GLY-202原料药 化学、生产和控制（CMC）活动（目标1）、药理学（目标2）和毒性 研究（目标3）。执行拟议的目标将证明合成的可扩展性， 中试生产规模的重现性以及通过药理学和毒性确定的有效性和安全性 问题研究在第二阶段期间，聚糖治疗将提交孤儿药认定 应用程序.孤儿药地位的好处包括通过收费获得的重大经济利益 豁免和税收抵免的临床费用。此外，临床试验招募将 相对小意味着可以充分制备所需量的GLY-202 由Glycan Therapeutics提供。在IIb期研究中，我们将完成GMP生产， 制剂，提交IND申请并进行I期临床试验。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，通过靶向HMGB 1介导的 用一流的治疗方法治疗炎症

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.