HBI-002 to Prevent Vaso-Occlusive Crises in Sickle Cell Disease

项目总结/摘要 拟议项目的目标是评估气体变送器一氧化碳（CO）作为 一种使用新型口服制剂预防镰状细胞病（SCD）中血管闭塞危象（VOC）的药物 CO（HBI-002）。大量的体外和体内研究表明，CO具有细胞保护作用， 通过抗氧化、抗炎和抗细胞凋亡过程来发挥其特性。我们的SBIR第1阶段支持 一项研究得出的疗效数据与使用四种不同转基因镰刀的四项研究报告的数据相似 细胞小鼠模型，血红素加氧酶-1/CO途径是SCD的关键，表明低剂量的 CO是限制血管淤滞和下调炎症过程的新方法。这些 研究为CO在限制SCD发病率方面的潜在有益作用提供了令人信服的支持。 CO的安全性和耐受性已在8个成功完成的I期和II期研究中得到证实。 研究，包括在SCD患者中进行的两项Ib期研究，使用各种形式的CO给药。 此外，有10项正在进行的CO临床研究，使用各种形式的CO给药。的 在低水平的碳氧血红蛋白（COHb）下不存在CO毒性已经在文献中得到了很好的定义， 为患有HBI-002的SCD患者考虑的目标COHb水平提供支持性安全性数据。 HBI-002是一种CO液体制剂，正在开发用于预防SCD中的VOC。政府当局 通过口服HBI-002递送的确定剂量的CO的量使得CO进一步发展为 同时避免了与先前研究的吸入或静脉注射相关的问题， 管理载体金属CO，包括环境安全性，剂量和遵守慢性 在一些实施方案中，本发明的组合物可用于评价给药（吸入CO）和载体分子毒性、稳定性和生物利用度（载体-金属结合CO）。 啮齿类动物口服HBI-002的药代动力学和药效学研究表明， 证明了概念验证的可行性、耐受性和生物利用度。下一步的发展是 评价机制、临床前毒理学和临床安全性、耐受性、药代动力学和 HBI-002在镰状细胞病中的进一步开发的药效学特征。

PROJECT SUMMARY/ABSTRACT The goal of the proposed project is to evaluate the potential of the gasotransmitter carbon monoxide (CO) as an agent to prevent Vaso-Occlusive Crises (VOCs) in Sickle Cell Disease (SCD) using a novel oral formulation of CO (HBI-002). Numerous studies, both in vitro and in vivo, demonstrate that CO has cytoprotective properties through anti-oxidant, anti-inflammatory and anti-apoptotic processes. Our SBIR Phase 1 supported research has produced efficacy data similar to that reported in four studies using four different transgenic sickle cell mouse models that the heme oxygenase-1/CO pathway is key in SCD, demonstrating that low doses of CO are a novel approach to limiting vascular stasis and down-regulating inflammatory processes. These studies provide compelling support for a potential beneficial role for CO in limiting the morbidity of SCD. The safety and tolerability of CO has been demonstrated in eight successfully completed Phase 1 and Phase 2 studies, including two Phase 1b studies in SCD patients, using a variety of forms of CO administration. Moreover, there are ten ongoing clinical studies with CO, using various forms of CO administration. The absence of toxicity of CO at low levels of carboxy-hemoglobin (COHb) has been well defined in the literature, providing supportive safety data for the targeted COHb levels being considered for SCD patients with HBI-002. HBI-002, a liquid formulation of CO, is being developed for the prevention of VOCs in SCD. The administration of a defined dose of CO delivered by oral administration of HBI-002 enables the further development of CO as a therapeutic while obviating the problems associated with previously studied inhaled or intravenously administered carrier-metal CO, including environmental safety, dosing and compliance with chronic administration (inhaled CO) and carrier molecule toxicity, stability, and bioavailability (carrier-metal bound CO). Pharmacokinetic and pharmacodynamic studies in rodents with orally administered HBI-002 have demonstrated proof-of-concept feasibility, tolerability, and bioavailability. The next step in development is to evaluate the mechanistic, preclinical toxicologic, and clinical safety, tolerability, pharmacokinetic, and pharmacodynamic profile of HBI-002 for further development in sickle cell disease.