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

项目摘要/摘要 遗传性血色沉着症(HH)是美国最常见的遗传性疾病之一，影响 100万人，主要是北欧后裔。患有HH的人无法产生海普西丁， 因此，会经历饮食中铁的过度吸收。过量的铁储存在组织和器官中，导致 临床铁超载和严重的健康问题，包括肝硬变和心力衰竭。静脉切开术是主要的 需要维持性治疗的高血压患者血清铁蛋白水平的管理 一生中平均每年抽血治疗4-6次。虽然抽血是安全的，但它是安全的 患者不能很好地耐受。这会导致长期依从性差，严重的器官损伤，以及 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，尽管研究探索了药物干预的潜力 对于铁超载(例如，全身铁络合疗法、蛋白质替代疗法、基因疗法)，很少有人 已被临床翻译，没有一种已商业化用于铁超载的慢性管理 安全和成本问题。因此，非常需要一种安全、方便的干预措施，即 静脉切开术治疗慢性高血压病患者铁超载的有效替代方法。在这 在这个项目中，我们将开发一种口服剂量的非吸收铁络合剂BBI-001，它可以将饮食中的铁结合在 通过排泄粪便消除小肠，慢性维持小鼠血清铁蛋白水平 HH患者。BBI-001的初步研究证实了其在小动物身上的作用机制 模型试验表明，它具有不吸附、铁结合能力强、选择性快等特点。 胃肠道吸收前结合铁的动力学。这项第一阶段SBIR研究有两项 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量毒性研究 验证BBI-001‘S每日多剂量给药的安全性。具体目标2将专注于快速临床 通过准备支持IND(新药研究)前会议的一揽子计划来翻译BBI-001 FDA对BBI-001和推进化学、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作为第一个也是唯一一个非 中毒性铁络合疗法和维持性静脉切开术安全有效的替代治疗 高血压患者血清铁蛋白水平的维持。慢性高血压病患者铁超载的治疗 BBI-001将导致改善依从性并更一致地维持血清铁蛋白水平，领先 降低器官损伤和相关并发症的风险，降低医疗成本，改善长期 HH患者的预后。

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.