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

改进的口服 P-选择素阻滞剂用于预防性镰状细胞病治疗

基本信息

批准号：
8780313
负责人：
Stephen H. Embury
金额：
$ 22.6万
依托单位：
VANGUARD THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8780313
关键词：
Accounting Activated Partial Thromboplastin Time measurement Acute Acute Pain Adhesions Adverse effects Affect Anticoagulants Binding Biological Assay Biological Availability Blood Blood Vessels Blood flow Cell Adhesion Molecules Cellular Assay Cessation of life Clinic Clinical Data Clinical Trials Data Defect Development Disease Dose Drug Formulations Drug Kinetics Erythrocytes Event Exclusion Factor Xa Fractionation Frequencies Functional disorder Generations Goals Grant HL-60 Cells Hemoglobin Heterogeneity Human Impairment In Vitro Individual Inherited Legal patent Macaca fascicularis Marketing Modeling Molecular Molecular Weight Monkeys Morbidity - disease rate Mus Oral P-Selectin Pain Parents Patients Pentosan Polysulfate Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Preclinical Testing Prevention Production Property Prophylactic treatment Prothrombin time assay Quality of life Radioactivity Radiolabeled Recombinants Sickle Cell Sickle Cell Anemia Sickle Hemoglobin Small Business Innovation Research Grant Sodium Sodium Compounds Symptoms Testing Therapeutic Thrombin Time Assay United States absorption base compliance behavior disability hydroxyurea improved pill polymerization premature prevent prophylactic public health relevance radiotracer scale up sickling theories

项目摘要

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.

描述（由申请人提供）：镰状细胞病（SCD）是一种治疗效果不佳的衰弱性疾病，我们正在开发一种有前景的新型口服预防疗法。我们对药物存在迫切需求，因为全球数百万遗传性 SCD 患者（美国约 100,000 名）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缺陷，许多正在开发的药物的目标是治疗而不是预防急性事件。大多数 SCD 发病的原因是血流异常，尤其是微血管血流停止导致的急性疼痛危象。血流缺陷是由多种病理生理学引起的，包括几种与脱氧→镰状血红蛋白聚合→红细胞镰状化的典型顺序无关的病理生理学。基于内皮 P-选择素对于持续损伤和急性血流停止至关重要的证据，我们的治疗针对的是这种粘附分子。体外和初步临床数据表明，戊聚糖多硫酸钠 (PPS) 可改善 SCD 的微血管血流量。然而，市售的 PPS 并不是理想的治疗方法，因为其口服生物利用度有限且作用持续时间有限。因此，我们制定了两个协同计划来开发改进的第二代 PPS-2，它将提供更高的口服生物利用度，因此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 给药频率并增强患者依从性。一项计划采用母公司 PPS 的直接制定；另一种方法采用 PPS 的分级分离，鉴定药学上优异的 PPS 级分，并配制最佳级分。该提案重点关注分馏策略。与普通 PPS 相比，较低分子量的 PPS 级分具有更好的口服生物利用度和更低的抗凝活性。我们首先将测试不同分子量的 PPS 级分，以确定具有强大 P-选择素阻断活性的两个最低分子量级分和安全的抗凝活性。然后我们将在猴子中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代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 化合物来获得迄今为止 PPS 的最佳生物利用度/药代动力学数据，并首次获得 PPS 组分的此类数据。这些研究将确定最有利的 PPS 级分，并将其配制和开发为 PPS-2，并将能够申请物质组合物专利。我们的首要目标是通过向市场推出一种有效的口服 P-选择素阻断药物来改善 SCD 患者的生活质量，该药物可以长期服用，以防止镰状红细胞粘附在血管内壁，改善血液流动，并避免急性疼痛发作。该 I 期 SBIR 将为 PPS-2 配方和开发提供优质的 PPS 级分。随后的分馏、配方、体外和镰状细胞小鼠临床前测试、GMP 生产和 IND 备案将在 II 期 SBIR 拨款的支持下完成。