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

摘要：镰状细胞病(SCD)在美国主要困扰非裔美国人，加剧了现有的 健康差距。大约每13名非洲裔美国婴儿中就有1名出生时具有镰状细胞特征，约100,000人 患有SCD的个体。以及一系列不利的生理影响，导致痛苦的血管闭塞 危机(VOC)，患者的生活质量较差，预期寿命显著减少(只有54 年)。目前有几种药物是FDA批准的；然而，尽管它们有好处，但也有缺点。 羟基脲对两种基因型有效，仅占SCD患者的60%和疼痛的频率 发作次数只减少了50%。新药(L-谷氨酰胺，Crizanlizumab，Voxelotor)在治疗中缺乏改善 血红蛋白水平或VOCs数量缺乏减少。替代治疗，如慢性输血 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。 或者设置障碍，包括成本和寻找匹配的捐赠者。有一个巨大的需求尚未得到满足， 新颖的多模式SCD疗法，实现最佳的疗效、安全性和生活质量。为了满足这一需求， 血管视觉提出了一种硫化氧化非抗凝剂低分子肝素(S-NACH)来 提供广泛的生物活性而不会导致出血，这是一种常见的剂量限制效应 随着低分子肝素在临床上的应用。概念验证的体外和体内临床前研究 通过抗粘连、抗炎、抗疲劳等多种方式确立疗效， 血管抗血栓和内皮松弛。我们的皮下纳米制剂(VVP728)展示了 改进了SCD药效学。这项SBIR第二阶段建议进行IND研究，以确定耐受性 通过以下具体目标支持第一次人体试验(FIH)的纳米配方S-纳赫(VVP728)： 目标1.扩大制造规模以建立PK/PD并支持支持IND的研究。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 原料药(DS：S-NACH)和药品(DP：VVP728)。里程碑：(1)发展分析和生物分析 方法(2)在GLP下给予研究级DS(2 Kg)和DP(1.5 kg)；(3)测定PK和血管 DS与DP的大鼠抗血栓活性及Townes SCD小鼠PD模型的比较。目标2：确定GLP安全性 S-纳赫侧记。我们将进行剂量范围查找研究(7天)和GLP重复剂量研究(28 在啮齿动物(大鼠)和非啮齿动物(狗)中)以及在体外对蛋白质结合、转运蛋白和 CYP抑制，对HEK-293细胞Herg电流的影响，以及遗传毒性。活体中枢神经 将完成系统(CNS：大鼠)、呼吸系统(狗)和心血管(狗)的评估。里程碑： (1)建立S-NACH对转运蛋白和细胞色素P450的结合和抑制潜能，(2)确定靶点 毒性器官在FIH研究中的剂量选择；(3)建立S-NACH对小鼠的遗传毒性潜力 细菌回复突变和体外微核试验。

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.