Preparing BBI-001 as an oral, non-absorbed iron chelator for prevention of iron overload

项目总结/摘要 遗传性血色病（HH）是美国最常见的遗传性疾病之一， 100万人主要是北方欧洲人的后裔。患有HH的人不能产生hepcidin， 结果，经历了膳食铁的过量吸收。过量的铁储存在组织和器官中， 临床铁超载和严重的健康问题，包括肝硬化和心力衰竭。静脉切开术是主要的 用于管理HH患者血清铁蛋白水平的治疗，患者需要维持治疗 在其一生中，平均每年进行4-6次静脉切开术治疗。虽然放血术是安全的， 患者不能很好地耐受。这导致长期依从性差，严重的器官损伤， 严重健康状况的风险增加。药物治疗提供了一个有吸引力的替代方案， 维持性静脉切开术然而，尽管研究已经探索了药物干预的潜力， 对于铁过载（例如，全身性铁螯合疗法、蛋白质替代疗法、基因疗法），很少有 临床翻译，没有商业化的慢性管理铁过载，由于 安全和成本的问题。因此，非常需要一种安全、方便的干预措施， 是HH患者长期维持铁超负荷的一种有效的静脉切开术替代方法。在这 项目，我们将开发一种口服剂量，非吸收铁螯合剂，BBI-001，结合膳食铁在 小肠和消除它通过粪便输出慢性维持血清铁蛋白水平， 患者HH。BBI-001的初步研究已验证其在小动物中的作用机制 模型，并证明它是非吸收，具有高铁结合能力，选择性与快速 在胃肠道吸收之前结合铁的动力学。第一阶段SBIR研究有两个 具体目标：在具体目标1中，我们将完成大鼠临床前最大耐受剂量毒性研究 验证BBI-001在每天多次给药时的安全性。具体目标2将侧重于快速临床 翻译BBI-001，准备一个文件包，以支持IND（研究性新药）前会议， FDA的BBI-001，并通过推进化学，制造和控制（CMC）战略的准备 用于cGMP生产。该项目的长期目标是将BBI-001商业化，作为第一个也是唯一一个非 毒性铁螯合疗法和维持性静脉切开术的一种安全有效的替代方法 维持HH患者的血清铁蛋白水平。HH患者铁超负荷的长期治疗 BBI-001将改善依从性，更一致地维持血清铁蛋白水平， 降低器官损伤和相关并发症的风险，降低医疗费用，改善长期 HH患者的结局。

PROJECT SUMMARY/ABSTRACT Hereditary Hemochromatosis (HH) is one of the most common genetic disorders in the United States affecting 1 million people primarily of Northern European descent. People with HH are unable to produce hepcidin and, as a result, experience excess absorption of dietary iron. Excess iron is stored in tissues and organs, causing clinical iron overload and severe health issues, including cirrhosis and heart failure. Phlebotomy is the primary treatment for managing serum ferritin levels in patients with HH, with patients requiring maintenance phlebotomy treatments 4-6 times per year on average throughout their lifetime. While phlebotomy is safe, it is not well tolerated by patients. This leads to poor long-term compliance, significant organ damage, and increased risk of severe health conditions. Pharmacologic treatment offers an attractive alternative to maintenance phlebotomy. However, while studies have explored the potential of pharmacologic interventions for iron overload (e.g., systemic iron chelation therapy, protein replacement therapy, gene therapy), few have been clinically translated and none have been commercialized for chronic management of iron overload due to issues of safety and cost. As a result, there is a significant need for a safe, convenient intervention that is an effective alternative to phlebotomy for chronic maintenance of iron overload in patients with HH. In this project, we will develop an orally dosed, non-absorbed iron chelator, BBI-001, that binds dietary iron in the small intestine and eliminates it through fecal output for chronic maintenance of serum ferritin levels in patients with HH. Preliminary studies of BBI-001 have validated its mechanism of action in a small animal model and demonstrated that it is non-absorbed and has high iron binding capacity, and selectivity with rapid kinetics for binding iron prior to absorption in the gastrointestinal tract. This Phase I SBIR study has two Specific Aims: In Specific Aim 1, we will complete a preclinical Maximum Tolerated Dose toxicity study in rats to validate BBI-001’s safety when multiple doses are given per day. Specific Aim 2 will focus on rapid clinical translation of BBI-001 by preparing a package to support a pre-IND (Investigational New Drug) meeting with the FDA for BBI-001 and by advancing Chemistry, Manufacturing, and Controls (CMC) strategy in preparation for cGMP production. The long-term goal of this project is to commercialize BBI-001 as the first and only non- toxic iron chelation therapy and a safe and effective alternative to maintenance phlebotomy for chronic maintenance of serum ferritin levels in HH patients. Chronic treatment of iron overload in HH patients with BBI-001 will result in improved compliance and more consistent maintenance of serum ferritin levels, leading to lower risk of organ damage and related complications, reduced healthcare costs, and improved long-term outcomes in patients with HH.