Twice-Weekly Subcutaneous Liposome Chelator to Treat Transfusional Iron Overload

每周两次皮下脂质体螯合剂治疗输血铁过载

• 批准号: 9043150
• 负责人: Mark Eamon Hayes
• 金额: $ 95.67万
• 依托单位: ZONEONE PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-05 至 2018-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043150
• 关键词: Adult; Adverse effects; Blood; Blood Transfusion; Body Weight; Bone Marrow; Cause of Death; Cessation of life; Chelating Agents; Chelation Therapy; Child; Childhood; Clinical; Clinical Pathology; Clinical Trials Design; Cyclic GMP; DNA Sequence Alteration; Data; Deferoxamine; Development; Disease; Documentation; Dose; Drug Kinetics; Encapsulated; Endocrine Glands; Erythrocyte Transfusion; Erythrocytes; Excision; FDA approved; Formulation; Frequencies; Funding; Goals; Heart; Heart failure; Hematological Disease; Hemoglobin; Hepatocyte; Human; Hyaluronidase; Individual; Infusion procedures; Injectable; Injection of therapeutic agent; Iron; Iron Overload; Kupffer Cells; Lead; Life; Liposomes; Liver; Longevity; Lysosomes; Macaca fascicularis; Manufacturer Name; Marketing; Maximum Tolerated Dose; Mole the mammal; Morbidity - disease rate; Mus; Mutation; Myocardium; Organ; Outcome; Pain; Pathology; Patients; Phagocytosis; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Pre-Clinical Model; Preparation; Primates; Process; Production; Qualifying; Rattus; Recovery; Reporting; Research; Rivers; Rodent; Route; Safety; Schedule; Sickle Cell; Sickle Cell Anemia; Site; Spleen; Tablets; Technology; Technology Transfer; Testing; Thalassemia; Therapeutic; Time; Tin; Toxic effect; Toxicokinetics; Toxicology; Transfusion; Treatment outcome; Urinalysis; Validation; Work; base; cell type; compliance behavior; design; food consumption; improved; iron chelation therapy; macrophage; meetings; nanoliposome; nanosized; nonhuman primate; novel; pre-clinical; preclinical efficacy; programs; public health relevance; safety study; scale up; subcutaneous; theories

 DESCRIPTION (provided by applicant): We have devised a novel, stable nanoliposome encapsulated desferoxamine (DFO) formulation (LDFO) for the treatment of iron overload. Data from a pre-clinical model of iron-overload indicates that LDFO is over 50% efficient at removing iron on a molar basis, which is over 4 fold higher than the most efficient approved iron chelator. Our nanoliposomal iron chelator formulation has the potential to be a significant therapeutic improvement because heart failure remains one of the more common causes of death in children and adults with red blood cell (RBC) transfusion dependent thalassemia or sickle-cell disorders. Long-term transfusions result in the potentially lethal accumulation of iron in the body due to its release from the transfused RBC. Humans are unable to eliminate such large amounts of iron, and consequently the additional iron accumulates to toxic levels in the liver, spleen endocrine organs, and ultimately the heart. Chelation therapy is prescribed to reverse iron accumulation in these patients. Unfortunately, marketed chelators are inefficient and have severe drawbacks which include long painful infusions of desferoxamine, the necessity to take large tablets with potential life-threating adverse effects (Exjade, Novartis) or twice (Ferriprox, ApoPharma) daily. Thus, iron overload patients have poor compliance and poor outcomes. A more efficient iron removing medication could dramatically improve treatment outcomes. Patience compliance is a major factor limiting the therapeutic benefit of existing iron chelators. LDFO has the potential to revolutionize treatment for iron overload diseases; higher iron removal efficiency will lead to fewer doses, given over a shorter time period. Completion of this research could lead to a dramatically improved treatment that increases compliance rates and provides substantially better management of iron overload than current treatments in pediatric and adult thalassemia and sickle cell anemia patients. To move the LDFO formulation towards clinical development, we will pursue four specific aims. In specific aim 1, we will conduct non-GLP iron removal efficacy, pharmacology and toxicology studies in rodents of the lead LDFO followed by a pilot toxicology study in non-human primates (NHP) to assess the efficacy and safety of the LDFO formulation. In specific aim 2, we develop a process scale up, pilot manufacturing and technology transfer of LDFO to a qualified cGMP manufacturer. In specific aim 3, we will prepare preclinical and CMC documentation for a pre-IND meeting with the FDA. In specific aim 4, we undertake GLP-toxicity and toxicokinetic studies of a GMP LDFO formulation in NHP, as required by the FDA. The data generated in this research will form a large part of an IND package and will also inform the Phase 1 clinical trial design for LDFO.

 描述（由申请人提供）：我们设计了一种新型、稳定的纳米脂质体封装的去铁胺（DFO）制剂（LDFO），用于治疗铁过载。来自铁超载临床前模型的数据表明，LDFO 在摩尔基础上去除铁的效率超过 50%，比最有效的经批准的铁螯合剂高 4 倍以上。我们的纳米脂质体铁螯合剂配方有可能显着改善治疗效果，因为心力衰竭仍然是患有红细胞 (RBC) 输血依赖性地中海贫血或镰状细胞病的儿童和成人的更常见死亡原因之一。长期输血会导致铁在体内蓄积，可能致命 由于它从输注的红细胞中释放出来。人类无法消除如此大量的铁，因此额外的铁在肝脏、脾脏内分泌器官以及最终的心脏中积累到有毒水平。螯合疗法用于逆转这些患者的铁积累。不幸的是，市售的螯合剂效率低下，并具有严重的缺点，包括长期痛苦地输注去铁胺、需要服用大片剂并可能危及生命的副作用（Exjade、诺华）或两次（Ferriprox、 ApoPharma) daily.因此，铁超负荷患者的依从性差且预后差。更有效的除铁药物可以显着改善治疗效果。耐心依从性是限制现有铁螯合剂治疗效果的主要因素。 LDFO 有潜力彻底改变铁过载疾病的治疗；更高的除铁效率将导致在更短的时间内给予更少的剂量。这项研究的完成可能会显着改善治疗方法，提高依从率，并比目前对儿童和成人地中海贫血和镰状细胞贫血患者的治疗提供更好的铁过载管理。为了将 LDFO 制剂推向临床开发，我们将追求四个具体目标。在具体目标 1 中，我们将在主要 LDFO 的啮齿动物中进行非 GLP 除铁功效、药理学和毒理学研究，然后在非人类灵长类动物 (NHP) 中进行试点毒理学研究，以评估 LDFO 制剂的功效和安全性。在具体目标 2 中，我们开发了 LDFO 的工艺放大、试生产和技术转让给合格的 cGMP 制造商。在具体目标 3 中，我们将为与 FDA 举行的 IND 前会议准备临床前和 CMC 文件。在具体目标 4 中，我们按照 FDA 的要求，对 NHP 中的 GMP LDFO 制剂进行 GLP 毒性和毒代动力学研究。这项研究产生的数据将构成 IND 包的很大一部分，也将为 LDFO 的一期临床试验设计提供信息。