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）：镰状细胞疾病（SCD）是一种不良治疗的衰弱状况，我们正在开发一种有希望的新口服预防性疗法。我们的药物存在可怕的需求，因为数百万在全球遗传了SCD的患者，在美国约有100,000名患者，继续患有情节性疼痛，残疾和过早死亡。 羟基脲治疗具有明显的缺陷，许多正在开发目标治疗的药物，而不是预防急性事件。大多数SCD发病率的原因是血流异常，特别是由于微血管流量停止而导致的急性疼痛危机。 血流有缺陷来自多种病理生理，其中包括几种独立于去氧合的范式序列 - >镰状血红蛋白聚合 - >红细胞疾病。基于证据表明内皮P-选择素对持续的损伤和流动急性停止至关重要，我们将其靶向这种粘附分子。 体外和初步临床数据表明，五峰多硫酸钠（PPS）改善了SCD中的微血管血流。 但是，由于其边际口服生物利用度和有限的作用持续时间，市售PPS并不是理想的治疗。因此，我们已经设计了两个协同计划，以开发改进的第二代PPS-2，这些计划将提供增加的口服生物利用度，以便所有患者都将获得治疗量的PPS和延长的吸收，因此PPS给药的频率将降低并提高患者合规性。 一个计划采用直接配方父pps； 另一种采用PPS的分级，药物优质pps分数的鉴定以及最佳分数的配方。 该提案侧重于分馏策略。 较低的分子量PPS分数比未分流的PPS具有更好的口服生物利用度和抗凝活性更低。 我们首先将测试不同分子称重的PPS级分，以识别具有强大P-选择蛋白阻断活性的两个最低分子量分数 和安全的抗凝活性。然后，我们将测试这两种猴子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的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，首先是PPS级分的DAT。 这些研究将确定要作为PPS-2制定和开发的最有利的PPS分数，并能够提交物质专利的组成。 我们的总体目标是通过将有效的口服P-选择蛋白阻断药物推销长期给药，以防止镰状红细胞粘在血管内膜上，改善血液FLW并避免急性疼痛发作，从而改善SCD患者的生活质量。 I阶段I SBIR将为PPS-2公式和开发提供优质的PPS分数。 随后的分馏，配方，体外和镰状细胞小鼠的临床前测试，GMP的产生和IND归档，可以支持II期SBIR赠款。