Development of heparan sulfate-based therapeutics to treat inflammatory diseases

摘要 每周有6000多万美国人服用对乙酰氨基酚(APAP)。 不幸的是，过量的APAP会导致肝脏毒性，并导致超过一半的急性 美国的肝功能衰竭病例。N-乙酰半胱氨酸是APAP过量的唯一解毒剂， 如果在APAP摄入后10小时内服用，则有效。然而，许多患者并没有去寻找 N-乙酰半胱氨酸治疗窗口期的治疗。目前，肝脏移植是 对于这些出现较晚的患者，唯一可用的治疗选择。APAP毒性是一个主要原因 在美国和世界范围内用于肝脏移植。 这个SBIR二期项目的目标是开发一种抗炎的合成硫酸乙酰肝素 低聚糖，GLY-202，用于APAP过量患者，特别是迟发性患者。甘氨酸- 202是经过化合物优化研究后选定的，旨在找出更小、更容易 在APP过量模型中，合成具有体内疗效的寡糖，而不是18-聚体。 与18-聚体不同，GLY-202的合成可以用更短的合成路线实现， 大大降低了生产成本，并减少了显著的商业化障碍。 这一第二阶段将侧重于使IND成为可能的研究，包括GLY-202药物 化学、制造和控制(CMC)活动(目标1)、药理(目标2)和毒性 研究(目标3)。执行拟议的目标将展示综合可扩展性和 中试生产规模的重复性以及药理和毒性的有效性和安全性 学习。在第二阶段期间，葡聚糖治疗公司将提交孤儿药物名称 申请。孤儿药物地位的好处包括通过收费获得显著的经济利益 临床费用的减免和税收抵免。此外，临床试验招募将是 相对较小的意味着可以充分制备所需的GLY-202量 由葡聚糖治疗公司提供。在第二阶段的研究中，我们将完成GMP的制造， 处方，提交IND申请和进行第一阶段临床试验。这个项目的成功 靶向HMGB1介导的HMGB1将为治疗药物性肝毒性提供新的途径 炎症与一流的治疗方法。

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.