Improved Oral P-selectin Blocker for Prophylactic Sickle Cell Disease Therapy

摘要 镰状细胞病(SCD)是一种治疗不当的遗传性衰弱疾病，先锋治疗公司， 公司正在开发一种前景看好的新的长期口服疗法。对我们的药物存在着迫切的需求，因为数百万人 全球SCD患者和美国约89,000名SCD患者继续遭受阵发性疼痛发作、残疾和 过早死亡。目前的治疗方法有明确的局限性，许多药物正在开发目标中 解决而不是预防突发事件。大多数SCD的发病是由血流异常引起的； 非常严重的疼痛危机是由微血管血流停止引起的。虽然范例顺序是 脱氧诱导的镰状血红蛋白聚合和红细胞镰状是镰状细胞所必需的 贫血，这不足以解释导致疾病的血液流动障碍。几种病理生理学 损害血流的是非聚合反应的；急性疼痛血管闭塞发作的频率 与最易生病的红细胞(RBC)的数量无关，而与最易生病的红细胞(RBC)的数量相关 令人恶心的，最粘稠的红细胞。因为镰刀状红细胞与内皮P-选择素的黏附是损伤的关键 和急性血流停止，我们的治疗针对的是P-选择素。体外、体内和初步的 临床数据显示，P-选择素阻滞剂戊聚糖多硫酸钠(PPS)可改善微血管血液 流入SCD。然而，商业化的PPS并不是理想的SCD治疗方法，因为它的口腔边缘 生物利用度和有限的作用时间。一项美国专利申请已经提交，要求改进第二种- 一代PPS成分(VTI-1968)，具有更强的P-选择素封闭活性，没有更强的抗凝剂 活性，和更大的口服BA与PPS相比。 资助这项第二阶段的SBIR提案将支持支持IND的活动，以开发一种高级药物产品， 促进每日单次给药和患者依从性。需要支持的活动包括验证P-选择素 在小鼠体内阻断活性；设计和制定VTI-1968的剂型以增加吸收 并延长活性；优化生物利用度、药动学、药效学；并进行试点 在实验动物身上的毒理研究，所有的剂型。这些活动将推动我们的计划走向 生产良好生产规范(GMP)剂型，用作优化的GMP药材 在计划的人体试验中，为与FDA举行IND前会议做好准备，并促进我们为 临床试验。先锋的首要目标是通过为SCD患者带来 销售一种有效的口服P-选择素阻断药物，以防止镰刀状红细胞黏附在血管内膜上 血管，改善血液流动，避免急性疼痛发作。这一第二阶段的SBIR将进一步 开发一种能够实现这些目标并支持商业发展的药物。活动 将提高公司为产品商业化获得资金和合作伙伴的能力。

Abstract Sickle cell disease (SCD) is a poorly treated, inherited, debilitating condition for which Vanguard Therapeutics, Inc. is developing a promising new long-term oral therapy. A dire need exists for our drug, as the millions of SCD patients worldwide and ~89,000 in the US continue to suffer with episodic pain episodes, disability, and premature death. Current treatments have well-defined limitations, and many drugs under development target resolution rather than prevention of acute events. Most SCD morbidity is driven by abnormal blood flow; strikingly acute pain crises are caused by stoppage of microvascular flow. While the paradigmatic sequence of deoxygenation-induced sickle hemoglobin polymerization and red cell sickling is necessary for sickle cell anemia, it is not sufficient to explain the impaired blood flow that drives the disease. Several pathophysiologies that impair blood flow are polymerization-independent; the frequency of acute painful vaso-occlusive episodes does not correlate with the number of most sickleable red blood cells (RBC) but with the number of least sickleable, stickiest RBC. Because sickle RBC adhesion to endothelial P-selectin is critical to the impairment and acute stoppage of blood flow, we are targeting P-selectin with our therapy. In vitro, in vivo, and preliminary clinical data show that the P-selectin blocker pentosan polysulfate sodium (PPS) improves microvascular blood flow in SCD. However, commercially available PPS is not ideal SCD therapy because of its marginal oral bioavailability and limited duration of action. A US patent application has been filed for an improved second- generation PPS component (VTI-1968) that has greater P-selectin blocking activity, no greater anticoagulant activity, and greater oral BA compared to PPS. Funding this Phase-II SBIR proposal will support IND-enabling activities for a superior drug product that will facilitate single daily dosing and patient compliance. Activities to be supported include validating P-selectin blocking activity in vivo in mice; designing and formulating dosage forms of VTI-1968 to increase absorption and prolong activity; optimizing the bioavailability, pharmacokinetics, pharmacodynamics; and conducting pilot tox studies in experimental animals, all of the dosage forms. These activities will advance our program toward production of good manufacturing practices (GMP) dosage forms for use as an optimized GMP drug substance in planned human trials, foster readiness for a pre-IND meeting with the FDA, and facilitate our preparation for clinical trials. The overarching goal of Vanguard is to improve the quality of life of patients with SCD by bringing to market an effective oral P-selectin blocking drug that will prevent sickle red blood cell sticking to the lining of blood vessels, improve blood flow, and avert acute painful episodes. This Phase-II SBIR will further development of a drug that will accomplish those goals and support commercial development. The activities will advance the company's ability to gain funding and partners for product commercialization.