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

描述(由申请人提供)：镰状细胞病(SCD)是一种治疗不当的衰弱疾病，我们正在为其开发一种有前途的新的口服预防疗法。我们迫切需要我们的药物，因为全球数百万遗传了SCD的患者，在美国约10万人，继续遭受阵发性疼痛、残疾和过早死亡的痛苦。羟基脲治疗有明显的不足，许多药物正在研发中的靶向治疗而不是预防急性事件。大多数SCD的发病原因是血流异常，特别是由于微血管血流停止而导致的急性疼痛危象。血流缺陷是由多种病理生理因素引起的，其中包括几种与脱氧--镰状血红蛋白聚合-红细胞镰状--聚合顺序无关的病理生理机制。基于内皮P-选择素是持续损害和急性血流停止的核心证据，我们的治疗针对这种黏附分子。体外实验和初步临床数据表明，戊聚糖多硫酸钠(PPS)改善了SCD的微血管血流。然而，商业化的PPS并不是理想的治疗方法，因为它的口服生物利用度很低，作用时间有限。因此，我们设计了两个协同计划来开发改进的第二代PPS-2，这将提供更高的口服生物利用度，以便所有患者都将接受治疗量的PPS并延长吸收时间，从而减少PPS的给药频率，提高患者的依从性。一种方案采用直接配制母体PPS；另一种方案采用PPS的分级，鉴定药用上优越的PPS组分，并制定最佳组分。这项建议的重点是分馏战略。相对分子质量较低的PPS组分具有更好的口服生物利用度和较低的抗凝血活性。我们将首先测试不同分子量的PPS组分，以确定具有强大的P-选择素阻断活性的两个最低分子量组分 和安全的抗凝血活性。然后，我们将在猴子身上测试这两种药物的口服生物利用度和药代动力学，这是人类生物利用度和药物动力学的最佳非人类模型。这些研究将使用高剂量的放射性标记PPS化合物，以获得迄今为止PPS的最佳生物利用度/药代动力学数据，并首次获得PPS部分的此类数据。这些研究将确定最有利的PPS组分，作为PPS-2进行配方和开发，并将能够申请物质组合物专利。我们的首要目标是通过将一种有效的口服P-选择素阻断药物推向市场，从而改善SCD患者的生活质量，以防止镰刀状红细胞黏附在血管衬里，改善血液流动性，避免急性疼痛发作。这一第一阶段的SBIR将为PPS-2的配方和开发提供优质的PPS组分。随后的分级、配方、体外和镰状细胞小鼠的临床前试验、GMP生产和IND提交将在第二阶段SBIR拨款的支持下实现。

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is a poorly treated debilitating condition for which we are developing a promising, new oral prophylactic therapy. A dire need exists for our drug, as millions of patients who have inherited SCD world-wide, ~100,000 in the US, continue to suffer with episodic pain, disability, and premature death. Hydroxyurea treatment has clear-cut deficiencies, and many drugs under development target treatment rather than prevention of acute events. The cause of most SCD morbidity is abnormal blood flow, notably acute pain crises that result from stoppage of microvascular flow. Defective blood flow results from multiple pathophysiologies, includin several that are independent of the paradigmatic sequence of deoxygenation -> sickle hemoglobin polymerization -> red cell sickling. Based on evidence that endothelial P-selectin is central to ongoing impairment and acute stoppage of flow, we are targeting this adhesion molecule with our therapy. In vitro and preliminary clinical data show that pentosan polysulfate sodium (PPS) improves microvascular blood flow in SCD. However, commercially available PPS is not ideal therapy because of its marginal oral bioavailability and limited duration of action. Accordingly, we have devised two synergetic plans to develop improved second generation PPS-2 that will provide increased oral bioavailability so all patients will receive therapeutic amounts of PPS and prolonged absorption so that the frequency of PPS administration will be reduced and patient compliance enhanced. One plan employs direct formulation of parent PPS; the other employs fractionation of PPS, identification of pharmaceutically superior PPS fractions, and formulation of the optimal fraction. This proposal focuses on the fractionation strategy. Lower molecular weight PPS fractions have better oral bioavailability and less anticoagulant activity than unfractionated PPS. We first will test PPS fractions of different molecular weighs to identify the two lowest molecular weight fractions that have robust P-selectin blocking activity and safe anticoagulant activity. Then we will test those two for oral bioavailability and pharmacokinetics in monkeys, the best nonhuman model of human bioavailability and pharmacokinetics. These studies will use high doses of radiolabeled PPS compounds to obtain the best bioavailability/pharmacokinetic data for PPS to date and first such dat for PPS fractions. These studies will identify the most favorable PPS fraction to be formulated and developed as PPS-2 and will enable filing a composition of matter patent. Our overarching goal is to improve the quality of life of SCD patients by bringing to market an effective oral P-selectin blocking drug for long-term administration to prevent sickle red blood cell sticking to the lining of blood vessels, improve blood flw, and avert acute painful episodes. This Phase I SBIR will provide a superior PPS fraction for PPS-2 formulation and development. Subsequent fractionation, formulation, preclinical testing in vitro and in sickle cell mice, GMP production, and IND filing ill be achieved with support of a Phase II SBIR grant.