Novel Biodegradable Injectable Rod for Improved AMD Therapy

新型可生物降解注射棒可改善 AMD 治疗

• 批准号: 8647445
• 负责人: Peter A Campochiaro
• 金额: $ 18.74万
• 依托单位: GRAYBUG, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647445
• 关键词: 1 year old; Affect; Age related macular degeneration; Angiogenesis Inhibitors; Angiogenic Factor; Angiopoietin-2; Animal Model; Animals; Area; Avastin; Binding Proteins; Biological Process; Blindness; Blood Vessels; Bolus Infusion; Caliber; Chemicals; Clinical; Clinical Trials; Development; Dexamethasone; Digoxin; Dimensions; Disease; Dose; Doxorubicin; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Elderly; Electroretinography; Ensure; Evaluation; Exposure to; Exudative age-related macular degeneration; Eye; FDA approved; Frequencies; Functional disorder; Gene Expression; Generations; Goals; Growth; Growth Factor; Health Personnel; Implant; In Vitro; Injectable; Injection of therapeutic agent; Lead; Length; Libraries; Licensing; Lucentis; Mediating; Methods; Modeling; Mus; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Phase; Pigments; Polyethylene Glycols; Polymers; Production; Protein Array; Proto-Oncogene Proteins c-sis; Retina; Retinal; Rodent; Safety; Saline; Scheme; Shapes; Solubility; Stimulus; Surface; System; Technology; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Treatment Efficacy; Treatment Protocols; Vascular Endothelial Growth Factors; Visual; Visual impairment; angiogenesis; base; bevacizumab; comparative efficacy; copolymer; efficacy evaluation; human VEGF protein; hypoxia inducible factor 1; improved; inhibitor/antagonist; mouse model; nanoparticle; neovascular; neovascularization; novel; ocular neovascularization; particle; phase 2 study; public health relevance; ranibizumab; receptor; retinal rods; rho; safety study; scale up; screening; sebacic acid; small molecule; transcription factor

ABSTRACT Age-related macular degeneration (AMD) is the leading cause of blindness in older adults with the neovascular form of the disease (NVAMD) mainly responsible for severe vision loss. Current NVAMD treatments involve repeated intraocular injections of biologics that neutralize vascular endothelial growth factor (VEGF), an important NV stimulus. Aflibercept, approved in late 2011, provides an incremental benefit over ranibizumab and bevacizumab, as it may reduce injection frequency to every 2 months, from the monthly treatment regimen recommended for the other anti-VEGF agents. However, intraocular injection frequencies of 6-12 times a year remain a major burden on patients and health care providers. GrayBug is developing a novel, long-lasting, fully biodegradable drug-polymer conjugate injectable rod for AMD envisioned to require infrequent administration and improve treatment efficacy. The drug-polymer conjugate has a unique mechanism of action, the inhibition of hypoxia-inducible factor-1 (HIF-1)-regulated gene expression. HIF-1 induces the expression of multiple effectors of ocular NV including VEGF, platelet-derived growth factor-B (PDGF-B), VEGF and PDGF-B associated receptors, stromal derived growth factor-1 (SDF-1), and angiopoietin-2 (Ang2), all demonstrated to be involved in NVAMD pathophysiology. Indeed, blockade of one or more of these in addition to VEGF provides enhanced efficacy in animal models and clinical trials. The drug-polymer conjugate (DXR-PSA-PEG3) contains doxorubicin (DXR), a potent HIF-1 inhibitor, covalently conjugated to sebacic acid (SA) within a copolymer of poly(sebacic acid)-(polyethylene glycol)3 (PSA-PEG3). DXR-PSA-PEG3 particles release DXR as a DXR-SA conjugate slowly over time. DRX-SA has reduced solubility compared to free DXR, ensuring the drug does not reach toxic levels in the eye. Like free DXR, DXR-SA reduces VEGF, PDGF-B, and SDF-1 in the ischemic retina and unlike specific VEGF antagonists, such as ranibizumab or aflibercept, DXR-SA causes regression of preexisting NV. The suppression AND regression of NV is a major advantage that can result in increased efficacy and prolonged duration of effect. A first generation DXR-PSA-PEG3 nanoparticle formulation (0.65 ¿m) displayed in vitro release of only six days but suppressed ocular NV in human VEGF transgenic mice for 5 weeks, more than twice as long as ranibizumab in this model. Importantly, no ocular toxicity of the first generation DXR-PSA-PEG3 particles was observed in rodents, even at 10-100-times the effective dose. GrayBug has an exclusive license to this promising technology. As the DXR-PSA-PEG3 particles degrade via surface erosion, reduction of the surface area will lead to an extended duration of drug release. Here, we propose to produce and fully characterize rod-shaped injectables composed of the DXR- PSA-PEG3 conjugate (Specific Aim 1) and test their duration of drug release and safety in rabbits (Specific Aim 2). Successful completion of this project will lead to a Phase II proposal focused on efficacy evaluations and long-term safety studies in large animals that will enable the filing of an IND. Our ultimate goal is to develop a DXR-PSA-PEG3 product requiring only 1-2 administrations to patients per year to effectively control NVAMD.

摘要 视网膜相关性黄斑变性（AMD）是老年人失明的主要原因， 这种疾病的形式（NVAMD）主要导致严重的视力丧失。目前的NVAMD治疗包括 反复眼内注射中和血管内皮生长因子（VEGF）的生物制剂， 重要的NV刺激。2011年底批准的阿柏西普提供了比雷珠单抗更大的益处 和贝伐单抗，因为它可以将注射频率从每月治疗方案减少到每2个月一次 推荐用于其他抗VEGF药物。然而，眼内注射频率为每年6-12次， 仍然是患者和卫生保健提供者的主要负担。GrayBug正在开发一种新颖，持久，完全 用于AMD的可生物降解的药物-聚合物缀合物可注射棒设想需要不频繁的给药 提高治疗效果。药物-聚合物缀合物具有独特的作用机制，即抑制作用。 低氧诱导因子-1（HIF-1）调控的基因表达。HIF-1诱导多种细胞因子的表达， 眼NV的效应物，包括VEGF、血小板衍生生长因子-B（PDGF-B）、VEGF和PDGF-B 相关受体，基质衍生生长因子-1（SDF-1）和血管生成素-2（Ang 2），均被证明与 参与NVAMD病理生理学。事实上，除了VEGF之外，阻断这些中的一种或多种也是有效的。 在动物模型和临床试验中提供增强的功效。药物-聚合物偶联物（DXR-PSA-PEG 3） 含有阿霉素（DXR），一种有效的HIF-1抑制剂，与癸二酸（SA）共价结合， 聚（癸二酸）-（聚乙二醇）3的共聚物（PSA-PEG 3）。DXR-PSA-PEG 3颗粒释放DXR， DXR-SA结合物。与游离DXR相比，DRX-SA具有降低的溶解度，从而确保 药物不会在眼睛中达到毒性水平。与游离DXR一样，DXR-SA可减少VEGF、PDGF-B和SDF-1， 与特异性VEGF拮抗剂如雷珠单抗或阿柏西普不同，DXR-SA导致缺血性视网膜 既存NV消退。NV的抑制和消退是一个主要优点，可以导致 增加功效和延长作用持续时间。第一代DXR-PSA-PEG 3纳米颗粒 制剂（0.65 μ m）显示仅6天的体外释放，但在人VEGF中抑制眼部NV 转基因小鼠5周，在该模型中是雷珠单抗的两倍多。重要的是， 在啮齿动物中观察到第一代DXR-PSA-PEG 3颗粒的毒性，即使是其10-100倍 有效剂量。GrayBug拥有这项有前途的技术的独家许可。作为DXR-PSA-PEG 3 颗粒通过表面侵蚀降解，表面积的减少将导致药物的持续时间延长 release.在这里，我们建议生产并充分表征由DXR-100组成的棒状注射剂。 PSA-PEG 3偶联物（特异性目的1），并测试其在兔中的药物释放持续时间和安全性（特异性目的 2）。该项目的成功完成将导致第二阶段的建议，重点是疗效评价， 在大型动物中进行长期安全性研究，以便能够提交IND。我们的最终目标是开发一种 DXR-PSA-PEG 3产品每年仅需1-2次给药即可有效控制NVAMD。