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 镰状细胞疾病（SCD）是一种治疗良好的，遗传性的，令人衰弱的疾病，先锋疗法， Inc.正在开发一种有希望的新长期口服疗法。我们的毒品存在恐怖需要，因为数百万 全球SCD患者，在美国，约有89,000名患者继续患有情节性疼痛发作，残疾和 过早死亡。当前治疗有明确的局限性，并且许多正在开发的药物目标 解决方案而不是预防急性事件。大多数SCD发病率是由异常的血流驱动的。 显着的急性疼痛危机是由微血管流量停止引起的。而 脱氧诱导的镰状血红蛋白聚合和红细胞疾病对于镰状细胞是必需的 贫血，不足以解释驱动疾病的血流受损。几种病理生理 这种损害血流是与聚合无关的。急性疼痛的血管结合发作的频率 与最可恶的红细胞（RBC）的数量不相关，而是与数量最少 可悲，最粘的RBC。因为镰状RBC对内皮P-选择素的粘附对于损害至关重要 和血流的急性停止，我们通过治疗靶向P-选择素。体外，体内和初步 临床数据表明，P-选择蛋白阻滞剂五角星多硫酸钠（PPS）改善了微血管血液 SCD流动。但是，由于口服边缘，市售PPS并不是理想的SCD疗法 生物利用度和行动持续时间有限。美国专利申请已提出改进的第二次 具有更大P-选择蛋白阻塞活性的生成PPS成分（VTI-1968），没有更大的抗凝剂 与PPS相比，活动和更大的口服BA。 资助这一II期SBIR提案将为卓越的药物提供指定的活动 促进单一每日给药和患者依从性。要支持的活动包括验证P-选择素 在小鼠体内阻止活性；设计和制定VTI-1968的剂型以增加吸收 和延长活性；优化生物利用度，药代动力学，药效学；并指挥飞行员 在实验动物中的托克斯研究，所有剂型。这些活动将使我们的计划朝着 生产良好的制造实践（GMP）剂型作为优化的GMP药物 在计划的人类试验中，培养与FDA预先开会的准备，并促进我们的准备 临床试验。先锋的总体目标是通过带来改善SCD患者的生活质量 销售有效的口服P-选择蛋白阻断药物，以防止镰状血细胞粘在 血管，改善血液流动并避免急性疼痛发作。这个阶段II SBIR将进一步 开发将实现这些目标并支持商业发展的药物。活动 将促进公司获得资金和合作伙伴进行产品商业化的能力。