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 老年性黄斑变性(AMD)是老年人新生血管致盲的主要原因 这种疾病的形式(NVAMD)主要导致严重的视力丧失。目前NVAMD的治疗包括 反复眼内注射中和血管内皮生长因子(VEGF)的生物制剂，以及 重要的内华达州刺激。2011年末获批的afLibercept提供了比ranibizumab更多的好处 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 推荐用于其他抗血管内皮生长因子药物。然而，眼内注射的频率为每年6-12次 仍然是患者和医疗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的生物可降解药物-聚合物共轭注射棒预计不需要频繁给药 提高治疗效果。药物-聚合物结合物具有独特的作用机制，即抑制 低氧诱导因子-1(HIF-1)调控的基因表达。缺氧诱导因子-1诱导血管内皮细胞表达 眼部NV的效应因子包括血管内皮生长因子、血小板衍生生长因子-B、血管内皮生长因子和血小板衍生生长因子-B 相关受体，基质衍生生长因子-1(SDF-1)和血管生成素-2(Ang2)都被证明是 参与NVAMD的病理生理学研究。事实上，除了血管内皮细胞生长因子外，还可以封锁其中一种或多种 在动物模型和临床试验中提供增强的疗效。药物-聚合物偶联物(DXR-PSA-PEG3) 含有阿霉素(DXR)，一种有效的HIF-1抑制剂，在 聚癸二酸-聚乙二醇3共聚物(PSA-PEG3)。DXR-PSA-PEG3颗粒释放DXR AS 随着时间的推移，DXR-SA结合缓慢。与游离DXR相比，DRX-SA的溶解度降低，确保了 药物在眼睛里不会达到有毒的水平。与游离DXR一样，DXR-SA可降低血管内皮细胞生长因子、PDGF-B和SDF-1 视网膜缺血和不同于特定的血管内皮生长因子拮抗剂，如雷尼比单抗或阿普利赛特，DXR-SA导致 先前存在的NV的回归。NV的抑制和回归是一个主要的优势，可以导致 提高了疗效，延长了有效期。第一代DXR-PSA-PEG3纳米粒子 0.65微米制剂在体外仅释放6天，但对人血管内皮生长因子的眼部NV有抑制作用 转基因小鼠5周，在这个模型中是雷尼比珠单抗的两倍多。重要的是，没有眼睛 在啮齿动物身上观察到第一代DXR-PSA-PEG3颗粒的毒性，即使在10-100倍于 有效剂量。GrayBug拥有这项前景光明的技术的独家许可证。作为DXR-PSA-PEG3 颗粒通过表面侵蚀而降解，表面积的减小会导致药物持续时间的延长 放手。在这里，我们建议生产和充分表征由DXR-组成的棒状注射剂- PSA-PEG3结合物(特异靶1)及其在兔体内的药物释放持续时间和安全性(特异靶 2)。该项目的成功完成将导致第二阶段的提案，重点是疗效评估和 对大型动物进行的长期安全研究，这将使IND申请成为可能。我们的最终目标是开发一种 DXR-PSA-PEG3产品每年只需给患者1-2次给药即可有效控制NVAMD。