Sulfated Non-Anticoagulant Heparin Nanoparticle (VVP728) for Sickle Cell Disease Management

用于镰状细胞病管理的硫酸化非抗凝肝素纳米颗粒 (VVP728)

基本信息

批准号：
10545218
负责人：
Bozena Korczak
金额：
$ 99.62万
依托单位：
VASCULAR VISION PHARMACEUTICALS COMPANY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10545218
关键词：
Accounting Adhesions Adopted Affect African American African American population Binding Proteins Blood Transfusion Blood Vessels Cardiovascular system Cells Cessation of life Chronic Clinical Complex Data Development Disease Disease Management Disease Progression Dose Dose-Limiting Endothelium FDA approved Fatigue Frequencies Functional disorder Genotype Glutamine Hematopoietic Stem Cell Transplantation Hemochromatosis Hemoglobin concentration result Hemorrhage Heparin Hispanic Americans Hospitalization In Vitro Individual Inflammation Lead Life Expectancy Low-Molecular-Weight Heparin Methods Micronucleus Tests Morbidity - disease rate Mutation Neuraxis Organ Organ failure Oxides Pain Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Phase I Clinical Trials Phase II/III Trial Physiological Property Quality of life Rattus Relaxation Research Resolution Rodent Safety Selectins Sickle Cell Anemia Sickle Cell Trait Small Business Innovation Research Grant Small Business Technology Transfer Research Sulfate Testing Therapeutic Toxic effect Toxicology Treatment Cost United Nations Vascular Diseases Vision World Health Organization alternative treatment cost disorder prevention first-in-human genotoxicity global health health disparity hydroxyurea improved in vivo manufacturing scale-up mortality mouse model multimodality nanoformulation nanoparticle novel novel therapeutics pharmacokinetics and pharmacodynamics polymerization pre-clinical preclinical study premature public health priorities respiratory secondary endpoint stroke risk subcutaneous therapeutic candidate treatment strategy vaso-occlusive crisis

项目摘要

Summary: Sickle cell disease (SCD) primarily afflicts African-Americans in the US, exacerbating an existing health disparity. Approximately 1 in 13 African-American babies is born with the sickle cell trait and ~100,000 individuals live with SCD. Along with a range of adverse physiological effects resulting in painful vaso-occlusive crises (VOC), patients suffer from poorer quality of life and a significantly decreased life expectancy (only 54 years). A handful of drugs are currently FDA approved; however, despite their benefits, there are drawbacks. Hydroxyurea is effective for two genotypes accounting for only 60% of SCD patients and the frequency of painful episodes is reduced by only 50%. Newer drugs (L-glutamine, crizanlizumab, voxelotor) lack improvement in hemoglobin levels or lack reduction in number of VOCs. Alternative treatments, such as chronic blood transfusion therapy or hematopoietic stem cell transplantation, can provide benefit but can also lead to serious complications or impose roadblocks including cost and finding matching donors. There is a significant unmet need for potent, novel multi-modal SCD therapeutics that achieve optimal efficacy, safety, and quality of life. To meet this need, Vascular Vision proposes a sulfated oxidized non-anticoagulant low molecular weight heparin (S-NACH) to provide an extensive range of bioactivities without causing bleeding, a common dose limiting effect associated with the clinical use of low molecular weight heparins. Proof-of-concept in vitro and in vivo preclinical studies have established efficacy through multiple modes including anti-adhesion, anti-inflammation, anti-sickling, vascular antithrombotic, and endothelial relaxation. Our subcutaneous nanoformulation (VVP728) demonstrated improved SCD pharmacodynamics. This SBIR Phase II proposes IND-enabling studies to determine tolerability of nanoformulated S-NACH (VVP728) in support of first in human trials (FIH) through the following Specific Aims: Aim 1. Scale up manufacturing to establish PK/PD and support IND-enabling studies. To support preclinical PK/PD and GLP toxicology testing, we will scale up the manufacturing of research grade drug substance (DS: S-NACH) and drug product (DP: VVP728). Milestones: (1) Develop analytical and bioanalytical methods, (2) Deliver research grade DS (2 kg) and DP (1.5 kg) under GLP, and (3) Determine PK and vascular antithrombotic activity in rats and PD in Townes SCD mouse model for DS vs DP. Aim 2: Determine GLP safety profile of S-NACH. We will conduct dose range finding studies (7 days) and GLP repeated dose studies (28 days) in rodent (rat) and non-rodent (dog) as well as in vitro assessments of protein binding, transporter and CYP inhibition, effect on hERG current in transfected HEK-293 cells, and genotoxicity. In vivo central nervous system (CNS: rats), respiratory (dogs), and cardiovascular (dogs) assessments will be completed. Milestones: (1) Establish protein binding and potential for inhibition of transporters and CYPs by S-NACH, (2) Identify target organs of toxicity to inform selection of dose in FIH study, and (3) Establish genotoxic potential of S-NACH in Bacterial-Reverse Mutation and In Vitro Micronucleus Assays.

摘要：镰状细胞病 (SCD) 主要影响美国的非裔美国人，加剧了现有的疾病健康差距。大约三分之一的非洲裔美国婴儿出生时就有镰状细胞特征，约 100,000 患有 SCD 的人。伴随一系列不良生理效应，导致痛苦的血管闭塞危机（VOC）时，患者的生活质量较差，预期寿命显着下降（仅 54 年）。目前有少数药物已获得 FDA 批准；然而，尽管有这些好处，但也有缺点。羟基脲对仅占 SCD 患者 60% 的两种基因型有效且疼痛频率发作次数仅减少 50%。新药（L-谷氨酰胺、crizanlizumab、voxelotor）缺乏改善血红蛋白水平或挥发性有机化合物数量缺乏减少。替代疗法，例如长期输血治疗或造血干细胞移植可以带来益处，但也可能导致严重的并发症或设置障碍，包括成本和寻找匹配的捐赠者。对有效的、新型多模式 SCD 疗法，可实现最佳疗效、安全性和生活质量。为了满足这种需求， Vascular Vision 提出了一种硫酸化氧化非抗凝低分子量肝素 (S-NACH) 提供广泛的生物活性而不引起出血，这是一种常见的剂量限制效应随着低分子肝素的临床应用。体外和体内临床前研究的概念验证已通过抗粘连、抗炎、抗镰状化等多种模式确立功效血管抗血栓和内皮松弛。我们的皮下纳米制剂 (VVP728) 证明改善SCD药效学。该 SBIR 第二阶段提出了支持 IND 的研究以确定耐受性纳米配方 S-NACH (VVP728) 通过以下具体目标支持首次人体试验 (FIH)：目标 1. 扩大生产规模，建立 PK/PD 并支持 IND 研究。支持临床前PK/PD和GLP毒理学测试，我们将扩大研究级药物的生产物质（DS：S-NACH）和药品（DP：VVP728）。里程碑：(1) 开发分析和生物分析方法，(2) 根据 GLP 提供研究级 DS (2 kg) 和 DP (1.5 kg)，以及 (3) 确定 PK 和血管 DS 与 DP 的 Townes SCD 小鼠模型中大鼠的抗血栓活性和 PD。目标 2：确定 GLP 安全性 S-NACH 简介。我们将进行剂量范围寻找研究（7 天）和 GLP 重复剂量研究（28 天）在啮齿动物（大鼠）和非啮齿动物（狗）中以及蛋白质结合、转运蛋白和蛋白质结合的体外评估 CYP 抑制、对转染 HEK-293 细胞中 hERG 电流的影响以及遗传毒性。体内中枢神经系统（中枢神经系统：大鼠）、呼吸系统（狗）和心血管（狗）评估将完成。里程碑： (1) 确定 S-NACH 的蛋白质结合和抑制转运蛋白和 CYP 的潜力，(2) 确定靶标 (3) 确定 S-NACH 在 FIH 研究中的潜在遗传毒性细菌反向突变和体外微核测定。