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: 9202918
• 负责人: Stephen H. Embury
• 金额: $ 166.82万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9202918
• 关键词: Acute; Acute Pain; Address; Adhesions; Animal Model; Animals; Anticoagulants; Biological Availability; Blood Vessels; Blood flow; CD2 gene; Cannulations; Cell Adhesion; Cessation of life; Clinical Data; Clinical Research; Clinical Trials; Computer Assisted; Data; Development; Disease; Dosage Forms; Dose; Drug Kinetics; Enhancers; Enteral; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Event; Excipients; Formulation; Fostering; Frequencies; Functional disorder; Funding; Future; Generations; Goals; Grant; Health Care Costs; Healthcare; Hemoglobin; Human; Impairment; In Vitro; Inherited; Knockout Mice; Legal patent; Macaca fascicularis; Marketing; Mediating; Monitor; Morbidity - disease rate; Mus; Oral; Oral Administration; P-Selectin; Pain; Patients; Pentosan Polysulfate; Pharmaceutical Preparations; Pharmacodynamics; Phase; Preparation; Prevention; Process; Product Approvals; Production; Qualifying; Quality of life; Rare Diseases; Rattus; Readiness; Research; Research Support; Resolution; Safety; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Site; Small Business Innovation Research Grant; Sodium; Stomach; Testing; Therapeutic; United States; absorption; abstracting; base; capsule; care burden; combinatorial; commercialization; compliance behavior; design; disability; disabling symptom; effective therapy; improved; in vitro Assay; in vivo; intravital microscopy; man; meetings; pill; polymerization; premature; prevent; programs; prophylactic; protective effect; prototype; research and development; research clinical testing; safety study; sickling

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.

抽象的 镰状细胞病 (SCD) 是一种治疗不当的遗传性衰弱性疾病，Vanguard Therapeutics、 Inc.正在开发一种有前途的新型长期口服疗法。对我们的药物存在着迫切的需求，因为数以百万计的人 全球范围内的 SCD 患者以及美国约 89,000 名患者继续遭受阵发性疼痛、残疾和 过早死亡。目前的治疗方法有明确的局限性，许多药物正在开发中 解决而不是预防急性事件。大多数 SCD 发病是由血流异常引起的； 显着的急性疼痛危机是由微血管流动停止引起的。虽然范式序列 脱氧诱导的镰状血红蛋白聚合和红细胞镰状化是镰状细胞所必需的 贫血，不足以解释导致疾病的血流受损。几种病理生理学 损害血流的物质与聚合无关；急性疼痛性血管闭塞发作的频率 与最多镰状红细胞 (RBC) 的数量无关，但与最少镰状红细胞的数量相关 镰状、粘性最强的红细胞。因为镰状红细胞与内皮 P-选择素的粘附对于损伤至关重要 和急性血流停止，我们的治疗目标是 P-选择素。体外、体内和初步 临床数据表明，P-选择素阻滞剂戊聚糖多硫酸钠（PPS）可改善微血管血液 SCD 中的流量。然而，市售的 PPS 并不是理想的 SCD 治疗方法，因为它的口服效果有限。 生物利用度和作用持续时间有限。已提交一项美国专利申请，用于改进的第二 新一代 PPS 成分 (VTI-1968)，具有更强的 P-选择素阻断活性，无需更强的抗凝剂 与 PPS 相比，活性更高，口服 BA 更高。 资助这一第二阶段 SBIR 提案将支持优质药物产品的 IND 启用活动，该产品将 促进每日单次给药和患者依从性。支持的活动包括验证 P-选择素 阻断小鼠体内的活性；设计和配制 VTI-1968 剂型以增加吸收 并延长活动时间；优化生物利用度、药代动力学、药效学；并进行试点 所有剂型均在实验动物中进行毒性研究。这些活动将推动我们的计划 生产良好生产规范 (GMP) 剂型，用作优化的 GMP 原料药 在计划的人体试验中，促进与 FDA 举行 IND 前会议的准备，并促进我们的准备工作 临床试验。 Vanguard 的总体目标是通过以下方式改善 SCD 患者的生活质量： 上市一种有效的口服 P-选择素阻断药物，可防止镰状红细胞粘附在细胞内壁上 血管，改善血液流动，避免急性疼痛发作。本次第二阶段 SBIR 将进一步 开发一种能够实现这些目标并支持商业开发的药物。活动内容 将提高公司获得产品商业化资金和合作伙伴的能力。