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

将 BBI-001 制备为口服非吸收铁螯合剂，用于预防铁过载

• 批准号: 10258539
• 负责人: Cory Berkland
• 金额: $ 29.94万
• 依托单位: BOND BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10258539
• 关键词: Affect; Age-Months; Animal Model; Animals; Binding; Biological Sciences; Chelation Therapy; Chemistry; Chronic; Chronic Care; Cirrhosis; Clinical; Data; Dietary Iron; Disease; Dose; Enterobactin; Europe; European; Feces; Ferritin; Gastrointestinal tract structure; Gel; Genetic Diseases; Goals; Health; Health Care Costs; Heart failure; Hereditary hemochromatosis; Intervention; Investigational Drugs; Investigational New Drug Application; Iron; Iron Chelating Agents; Iron Overload; Iron binding capacity measurement; Kinetics; Legal patent; Maintenance; Maximum Tolerated Dose; Mus; Oral; Organ; Outcome; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Phase; Phase Ib Clinical Trial; Polymers; Preparation; Prevention; Publishing; Rattus; Risk; Safety; Serum; Severities; Small Business Innovation Research Grant; Small Intestines; Structure; Time; Tissues; Toxic effect; Translating; United States; Venous blood sampling; absorption; base; cGMP production; clinical translation; commercial application; cost; crosslink; design; enzyme replacement therapy; experience; gene therapy; hepcidin; improved; iron absorption; iron chelation therapy; meetings; pre-clinical; preclinical efficacy; preclinical safety; side effect; standard of care; technological innovation

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.

项目摘要/摘要 遗传性血色素沉着病（HH）是美国最常见的遗传疾病之一 北欧下降100万人。 HH患者无法生产肝素，并且 结果，经验超过了饮食铁的滥用。过量铁被存储在组织和器官中，导致 临床铁超负荷和严重的健康问题，包括肝硬化和心力衰竭。静脉切开术是主要的 治疗HH患者血清铁蛋白水平的治疗，需要维持的患者 静脉切开术每年平均每年4-6次。虽然静脉切开术是安全的，但 患者的耐受性不佳。这导致长期依从性不佳，器官损坏明显和 严重健康状况的风险增加。药理治疗提供了一种吸引人的替代方案 维护静脉切开术。但是，尽管研究探讨了药理干预的潜力 对于铁超负荷（例如，全身铁螯合疗法，蛋白质替代疗法，基因疗法），很少有 是在临床上翻译而没有商业化以用于慢性管理铁超负荷 安全和成本问题。结果，非常需要安全，方便的干预措施 HH患者的铁重体长期维持铁超负荷的有效替代方法。在这个 项目，我们将开发一种口服剂量的，未吸收的铁螯合剂BBI-001，它结合了饮食中的铁 小肠并通过粪便输出消除它，以长期维持血清铁蛋白水平 HH患者。 BBI-001的初步研究已经验证了其在小动物中的作用机理 模型并证明它是未吸收的，具有高铁结合能力，并且选择性迅速 在胃肠道遭受苦难之前，具有结合铁的动力学。这一I阶段SBIR研究有两个 特定目的：在特定目标1中，我们将完成大鼠临床前的最大耐受剂量毒性研究 每天给出多剂时，要验证BBI-001的安全性。具体目标2将集中于快速临床 通过准备一套包装来支持与预先印度的（调查新药）会议的包装来翻译BBI-001 BBI-001的FDA并通过推进化学，制造和控制（CMC）策略来准备 用于CGMP生产。该项目的长期目标是将BBI-001商业化为第一个也是唯一的非 - 有毒的铁螯合疗法，是维持静脉静脉切开术的安全有效替代方案 维持HH患者血清铁蛋白水平。 HH患者的铁超负荷的长期治疗 BBI-001将改善合规性和更一致地维持血清铁蛋白水平，导致 降低器官损伤和相关并发症的风险，降低医疗保健成本并改善长期 HH患者的结果。