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

项目总结/摘要 该项目的目的是评估HBI-002的临床潜力，HBI-002是一种新型口服低剂量碳 一氧化碳（CO）药物产品，能够使用低剂量CO预防血管闭塞性危机（VOC）， 镰状细胞病（SCD）。许多临床前和临床研究表明，CO具有双重作用， 作用机制包括抗镰状化和抗炎过程。我们在临床前 在两种HBI-002转基因SCD小鼠模型中的有效性数据与使用HBI-002的三项研究中报道的相似。 四种不同的转基因SCD小鼠模型和其他低剂量CO给药模式， 证明低剂量的CO是限制血管淤滞、减少溶血和 下调炎症过程。此外，SCD的概念验证临床疗效研究 证明SCD疗效生物标志物的改善，流行病学证据也支持 低剂量CO治疗SCD的潜力。这些研究提供了令人信服的支持， HBI-002在限制SCD发病率中的作用。 在21个成功完成的阶段中，其他人已经证明了低剂量CO的安全性和耐受性。 在各种适应症中进行的1期和2期临床研究，包括在SCD患者中进行的2项1b期研究，使用 多种形式的CO给药。此外，目前正在进行低剂量CO的临床研究， 各种形式的CO给药，包括HBI-002的I期研究。CO的毒性在 低水平的碳氧血红蛋白（COHb）已在文献中得到很好的定义，表明潜在的 在上述研究中，COHb水平的安全范围较宽，获益：风险比适当， 是HBI-002 SCD患者考虑的目标COHb水平。然而，长期给药的障碍 先前的治疗性给药方法预防了低剂量CO的发展， 长期用于预防VOC的治疗剂。到目前为止，吸入的CO气体（iCO）和CO结合到载体 分子如血红蛋白（CORM，也称为CO前药）已经是本发明中选择的模式。 大多数研究。然而，这些其他形式的低剂量CO预计不是可行的治疗选择 对于长期给药，由于iCO存在压缩CO的意外暴露风险 气瓶以及控制剂量的困难，以及使用CORM时载体分子的毒性、稳定性和CO 释放特性，所有这些都被证明是发展的实质性障碍。 HBI-002是一种新型口服低剂量CO制剂，可在SCD中长期使用低剂量CO，目前正在研究中。 为预防SCD中的VOC而开发。通过口服给予低剂量的CO， HBI-002能够进一步开发低剂量CO作为治疗剂，同时避免了这些问题 与iCO或CORM相关。口服HBI-002的临床前研究已经证明- 概念有效性、安全性和生物利用度。这些临床前数据有力地表明了预防血管紧张素转换酶抑制剂的有效性。 SCD中的闭塞。在此应用中，我们将联合收割机的专业知识与其创新的 技术，并建议建立在令人信服的数据，研究概念的有效性，安全性和 图10示出了SCD受试者中HBI-002的药代动力学。

PROJECT SUMMARY/ABSTRACT The goal of the proposed project is to evaluate the clinical potential of HBI-002, a novel oral low dose carbon monoxide (CO) drug product, that enables the use of low dose CO to prevent Vaso-Occlusive Crises (VOCs) in Sickle Cell Disease (SCD). Numerous studies, both preclinical and clinical, demonstrate that CO has dual mechanisms of action including anti-sickling and anti-inflammatory processes. We have produced preclinical efficacy data in two transgenic SCD mouse models with HBI-002 similar to those reported in three studies using four different transgenic SCD mouse models and other modes of low dose CO administration, all of which demonstrate that low doses of CO are a promising approach to limiting vascular stasis, reducing hemolysis, and down-regulating inflammatory processes. In addition, proof of concept clinical efficacy studies in SCD demonstrated improvements in SCD efficacy biomarkers, and epidemiological evidence also supports the therapeutic potential of low dose CO in SCD. These studies provide compelling support for a potential beneficial role for HBI-002 in limiting SCD morbidity. The safety and tolerability of low dose CO has been demonstrated by others in 21 successfully completed Phase 1 and Phase 2 clinical studies in various indications, including two Phase 1b studies in SCD patients, using a variety of forms of CO administration. Moreover, there are ongoing clinical studies with low dose CO, using various forms of CO administration, including a Phase 1 study with HBI-002. The absence of toxicity of CO at low levels of carboxy-hemoglobin (COHb) has been well defined in the literature, indicating the potential for a wide safety margin and appropriate benefit:risk ratio at the COHb levels in the studies described above, which are the target COHb levels being considered for SCD patients with HBI-002. However, barriers to chronic dosing of CO with prior therapeutic administrative approaches have prevented the development of a low dose CO therapeutic used chronically for the prevention of VOCs. To date, inhaled CO gas (iCO) and CO bound to carrier molecules such as hemoglobin (CORMs, also termed CO prodrugs) have been the modalities of choice in the majority of studies. However, these other forms of low dose CO are not expected to be viable therapeutic options for chronic dosing due to, with iCO, the risk of inadvertent exposure from the presence of compressed CO cylinders as well as difficulties in controlling dosing and, with CORMs, carrier molecule toxicity, stability, and CO release characteristics, all of which have proven to be substantial barriers to development. HBI-002, a novel oral low dose CO drug product, enables the chronic use of low dose CO in SCD and is being developed for the prevention of VOCs in SCD. The administration of a low, defined dose of CO delivered by oral HBI-002 enables the further development of low dose CO as a therapeutic while obviating the problems associated with iCO or CORMs. Preclinical studies with orally administered HBI-002 have demonstrated proof- of-concept efficacy, safety, and bioavailability. These preclinical data strongly point to efficacy in preventing vaso- occlusion in SCD. In this application, we combine the expertise of Hillhurst with its innovative technology and propose to build on compelling data to study the proof of concept efficacy, safety, and pharmacokinetics of HBI-002 in SCD subjects.