Intrathecal Cyclosporin for the Treatment of Amyotrophic Lateral Sclerosis (ALS)

鞘内注射环孢素治疗肌萎缩侧索硬化症 (ALS)

• 批准号: 7782336
• 负责人: Jenny Karlsson
• 金额: $ 2.5万
• 依托单位: MAAS BIOLAB, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7782336
• 关键词: Affect; Amyotrophic Lateral Sclerosis; Animal Model; Animal Testing; Area; Authorization documentation; Biological Assay; Biomedical Research; Blood - brain barrier anatomy; Bolus Infusion; Brain; Chromatography; Clinical Trials; Continuous Infusion; Cyclosporins; Data; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Ensure; Guidelines; High Pressure Liquid Chromatography; Histology; Human; Immunosuppressive Agents; Implant; Infusion Pumps; Injectable; Injection of therapeutic agent; Intrathecal Space; Investigational Drugs; Life; Measurement; Measures; Monograph; Neuroprotective Agents; New Drug Approvals; Patients; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Pump; Research; Rodent; Role; Route; Safety; Sheep; Small Business Innovation Research Grant; Spinal Cord; Spinal Puncture; Testing; Toxicology; Translational Research; United States Food and Drug Administration; burden of illness; design; potency testing; pre-clinical; safety study

DESCRIPTION (provided by applicant): The scientific research proposed, the determination of pre-clinical stability, pharmacokinetics and toxicology testing of Maas BiolAB's proprietary cyclosporin intrathecal formulation, Mitogard(tm), will allow the company to file for Investigational New Drug (IND) approval with the Food and Drug Administration (FDA) and begin human clinical trials for amyotrophic lateral sclerosis (ALS). Mitogard(tm) is designed for delivery into the intrathecal space. Cyclosporin does not readily cross the blood brain barrier, thus intrathecal delivery is needed to reach affected areas of the brain and spinal cord. Though cyclosporin is an FDA approved active ingredient and its safety profile is known to the FDA, both the Mitogard(tm) formulation and proposed intrathecal route of administration are new requiring further stability and toxicology studies. Cyclosporin is a powerful neuroprotectant, separate from its traditional role as an immunosuppressant, and has shown efficacy in pre-clinical models of ALS, making it a promising candidate to reduce the burden of the disease and extend the life of ALS patients. GMP stability data will be gathered over two years, toward confirmation of product shelf life. SBIR Phase I (year one) testing will confirm the purity and concentration of cyclosporin in the formulation and stability will be measured up to 12 months (with up to 24 month measurements in Phase II of the fast-track proposal). Potency testing will be performed using a HPLC assay following the chromatography guidelines of the USP NF monograph on injectable cyclosporin. Rodent and sheep toxicology tests will ensure that Mitogard(tm) can be safely administered intrathecally. Maas BiolAB and Northern Biomedical Research have planned dose escalation studies via lumbar puncture in both the rodent and sheep to determine the maximal and optimal safe dosing ranges of Mitogard(tm), and will include the histology of the spinal cord and brain. These will be followed by GLP 28 day rodent and 90 day sheep continuous pump infusion studies. These toxicology studies will provide data to enable an IND first for lumbar bolus injection into the intrathecal space, followed by a second IND for continuous infusion via implanted drug delivery pump. Progression from first lumbar puncture to second pump delivery safety studies will satisfy FDA requirements of drug delivery progression. This translational research will bring cyclosporin, which is a powerful broad-spectrum neuroprotectant drug in animal models, from animal testing to approval for human clinical trials. If cyclosporin is found to be an effective neuroprotectant in humans, it could reduce suffering from amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). This research will allow the FDA to assess the safety and stability of cyclosporin in treating ALS and to give permission to start the first human ALS trials.

描述（由申请人提供）：Maas BiolAB 专有的环孢菌素鞘内制剂 Mitogard(tm) 所提出的科学研究、临床前稳定性、药代动力学和毒理学测试的测定，将使该公司能够申请研究性新药 (IND)获得美国食品和药物管理局 (FDA) 的批准，并开始针对肌萎缩侧索硬化症 (ALS) 的人体临床试验。 Mitogard(tm) 设计用于输送到鞘内空间。环孢菌素不易穿过血脑屏障，因此需要鞘内给药才能到达大脑和脊髓的受影响区域。尽管环孢菌素是 FDA 批准的活性成分，并且 FDA 已知其安全性，但 Mitogard(tm) 配方和拟议的鞘内给药途径都是新的，需要进一步的稳定性和毒理学研究。环孢菌素是一种强大的神经保护剂，有别于其作为免疫抑制剂的传统作用，并且已在 ALS 临床前模型中显示出疗效，使其成为减轻疾病负担和延长 ALS 患者生命的有希望的候选药物。 GMP 稳定性数据将在两年内收集，以确认产品的保质期。 SBIR 第一阶段（第一年）测试将确认制剂中环孢菌素的纯度和浓度，并将测量长达 12 个月的稳定性（快速通道提案的第二阶段测量长达 24 个月）。将按照 USP NF 注射用环孢菌素专着的色谱指南，使用 HPLC 测定进行效价测试。啮齿动物和绵羊毒理学测试将确保 Mitogard(tm) 可以安全地鞘内给药。 Maas BiolAB 和 Northern Biomedical Research 计划通过对啮齿动物和绵羊进行腰椎穿刺进行剂量递增研究，以确定 Mitogard(tm) 的最大和最佳安全剂量范围，并将包括脊髓和大脑的组织学研究。随后将进行 GLP 28 天啮齿动物和 90 天绵羊连续泵输注研究。这些毒理学研究将提供数据，以便首先进行腰椎推注注射到鞘内空间的 IND，然后进行第二次 IND 通过植入的药物输送泵进行连续输注。从第一次腰椎穿刺到第二次泵输送安全性研究的进展将满足 FDA 对药物输送进展的要求。这项转化研究将使环孢菌素（一种强大的广谱神经保护药物）在动物模型中从动物测试转向批准人体临床试验。如果发现环孢菌素是人类有效的神经保护剂，它可以减少肌萎缩侧索硬化症（ALS 或卢伽雷氏病）的痛苦。这项研究将使 FDA 能够评估环孢菌素治疗 ALS 的安全性和稳定性，并批准启动首次人体 ALS 试验。