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

• 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
• 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

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途的新口服预防性治疗方法。对我们的药物存在着迫切的需求，因为全球数百万患有遗传性SCD的患者，在美国约有100，000人，继续遭受阵发性疼痛，残疾和过早死亡。 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发病的原因是异常血流，特别是由微血管流动停止引起的急性疼痛危象。 血流缺陷由多种病理生理学引起，包括几种独立于脱氧->镰状血红蛋白聚合->红细胞镰状化的范例顺序。基于内皮P-选择素是持续性损伤和急性血流停止的核心的证据，我们的治疗靶向这种粘附分子。 体外和初步临床数据显示，戊聚糖多硫酸钠（PPS）可改善SCD的微血管血流。 然而，市售PPS由于其边际口服生物利用度和有限的作用持续时间而不是理想的治疗。因此，我们设计了两个协同计划，以开发改进的第二代PPS-2，其将提供增加的口服生物利用度，因此所有患者将接受治疗量的PPS和延长的吸收，从而降低PPS给药的频率并提高患者的依从性。 一种方案采用母体PPS的直接配方;另一种方案采用PPS的分级，鉴定药学上的上级PPS组分，并制定最佳组分。 该提案侧重于分级策略。 较低分子量的PPS馏分具有较好的口服生物利用度和较低的抗凝活性比普通PPS。 我们首先将测试不同分子量的PPS级分，以鉴定具有强大的P-选择素阻断活性的两种最低分子量级分 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，猴子是人体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，以获得迄今为止PPS的最佳生物利用度/药代动力学数据，以及PPS组分的首个此类数据。 这些研究将确定最有利的PPS组分，并将其配制和开发为PPS-2，并将能够提交物质组合物专利。 我们的总体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，以长期给药，防止镰状红细胞粘附在血管内壁，改善血液流动，避免急性疼痛发作。 该I期SBIR将为PPS-2制剂和开发提供上级PPS分数。 随后的分离、配制、体外和镰状细胞小鼠临床前试验、GMP生产和IND申报将在第二阶段SBIR资助的支持下实现。