Improved Adventitial Rapamycin Therapy for Peripheral Artery Restenosis

改进外膜雷帕霉素治疗外周动脉再狭窄

• 批准号: 8701363
• 负责人: Kirk Seward
• 金额: $ 108.86万
• 依托单位: MERCATOR MEDSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701363
• 关键词: Address; Affect; Albumins; American; Amputation; Angioplasty; Ankle; Arteries; Atherectomy; Atherosclerosis; Balloon Angioplasty; Binding; Biological; Biological Markers; Blood Circulation; Blood Vessels; Bypass; Carotid Arteries; Catheters; Cells; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Controlled Clinical Trials; Coronary; Coronary artery; Data; Deposition; Devices; Diabetes Mellitus; Disadvantaged; Dissection; Distal; Dose; Double-Blind Method; Drug Delivery Systems; Drug Formulations; Drug usage; Effectiveness; Enrollment; Epidemic; Event; FDA approved; Family suidae; Foreign Bodies; Freedom; Gangrene; Ground Substance; Healed; Human; Hyperplasia; Implant; Incidence; Individual; Infusion procedures; Injury; Insulin Resistance; Intervention; Investigational New Drug Application; Kinetics; Lead; Leg; Legal patent; Lesion; Limb structure; Lower Extremity; Medial; Metals; Methods; Morbidity - disease rate; Needles; Obesity; Operative Surgical Procedures; Outcome; Pain; Patients; Pericytes; Peripheral; Peripheral arterial disease; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Phase I Clinical Trials; Phenotype; Pilot Projects; Placebo Control; Play; Postoperative Period; Prevalence; Prevention; Procedures; Proliferating; Public Health; Rana catesbeiana; Randomized Controlled Clinical Trials; Recovery; Research; Role; Safety; Sirolimus; Slide; Smooth Muscle Myocytes; Societies; Stenosis; Stents; Structure of popliteal artery; Superficial Femoral Artery; Surface; Techniques; Testing; Therapeutic; Therapeutic Embolization; Time; Translating; Tunica Adventitia; Ulcer; Ultrasonography; Vascular Diseases; Vascular remodeling; Walking; adjudicate; aging population; animal data; base; claudication; clinical effect; cohort; commercialization; demographics; dosage; effective therapy; femoral artery; fibrous protein; healing; implantation; improved; indexing; innovation; limb amputation; nanoparticle; novel; phase 2 study; preclinical evaluation; preclinical study; prevent; public health relevance; renal artery; response; restenosis; success; thrombolysis

DESCRIPTION (provided by applicant): Peripheral artery disease (PAD) affects 9 to 12 million Americans [1] and 1.5 million will require an intervention (407,400 receive bypass or amputation; 1,080,000 receive angioplasty, stent or atherectomy) each year [3]. Unfortunately, only one-third of patients have a patent artery one year after balloon angioplasty of the femoral artery [4]. Bare metal stents [5-7] have eliminated elastic recoil and flow-limiting dissections bu have not significantly impacted restenosis due to intimal hyperplasia [3, 8-10]. Indeed, stents placed in the femoro- popliteal segment provide patency rates of only 54-63% at 1 year and 28-55% at 2 years [5, 7, 11-12], and drug eluting stents have fared no better than bare stents in eliminating restenosis [13-15]. Recently, use of drug-coated balloons in the peripheral artery has shown potential to improve patency without the need to implant stents [16]. However, the kinetics of luminal-based therapy (drug-eluting balloons and stents) place the maximal concentration of drug at the luminal-wall interface. This has the distinct disadvantage of hindering healing and re-endothelialization of the vessel. Recent data suggests that the adventitia plays a critical role in intimal hyperplasia, contributing to both neointimal cell volum and adverse remodeling. We have successfully completed the aims of Phase 1 research and in pre-clinical studies we have demonstrated non-toxic, efficacious doses of rapamycin, a well-known anti-restenotic agent in a novel nanoparticle formulation, delivered directly into the vascular adventitia through a percutaneous catheter at the time of angioplasty. This method avoids foreign body implantation and creates a high concentration in the adventitia and a lower concentration at the luminal surface. Mercator MedSystems has developed a catheter that slides a single needle through the vessel wall when a balloon is inflated, allowing direct therapeutic access to the adventitia. The catheter has been used in human pilot studies with successful adventitial delivery leading to cylindrical deposition of drugs around the vessel, creating a natural drug-eluting reservoir. We are now proposing to advance this research into human clinical trials, with Specific Aims of confirming safety while demonstrating the positive biological effect and clinical benefits of rapamycin delivered to the adventitia at the time of peripheral artery angioplasty. The innovative product that will be developed in this proposal is a combination device/drug therapy that will be broadly applicable to vascular disease. We believe that the significance of this proposal lies in the fact that (a) we are addressing a recalcitrant clinical problem (b) perivascular or adventitial therapy may be used as an adjunct to several common interventional revascularization techniques and (c) therapeutic success in PAD could be rapidly translated to settings such as coronary and renal artery restenosis or restenosis following coronary and peripheral bypass grafting. If these Phase 2 studies are successful, we intend to move into pivotal clinical trials and ultimately seek FDA approval for a novel combination product.

描述(申请人提供)：外周动脉疾病(PAD)每年影响900万至1200万美国人[1]，150万人需要干预(407400人接受搭桥或截肢；1080000人接受血管成形术、支架或动脉粥样硬化切除术)[3]。不幸的是，在股动脉球囊血管成形术一年后，只有三分之一的患者有动脉未闭[4]。裸金属支架[5-7]消除了弹性回弹力，限流性夹层对因内膜增生引起的再狭窄没有明显影响[3，8-10]。事实上，放置在股静脉段的支架1年的通畅率仅为54-63%，2年的通畅率为28-55%[5，7，11-12]，药物洗脱支架在消除再狭窄方面的效果并不比裸支架好[13-15]。最近，在外周动脉中使用药物涂层球囊显示了在不需要植入支架的情况下改善通畅性的潜力[16]。然而，基于管腔的治疗(药物洗脱球囊和支架)的动力学将药物的最大浓度放置在管腔-壁界面处。这有一个明显的缺点，即阻碍血管的愈合和再内皮化。最近的数据表明，外膜在内膜增生中起关键作用，导致新生内膜细胞体积增加和不良重塑。我们已经成功地完成了第一阶段研究的目标，在临床前研究中，我们已经证明了雷帕霉素无毒、有效剂量，这是一种新的纳米制剂中的知名抗再狭窄药物，在血管成形术时通过经皮导管直接输送到血管外膜。这种方法避免了异物植入，并在外膜产生高浓度，在管腔表面产生低浓度。墨卡托医疗系统公司开发了一种导管，当气球充气时，只需一根针就能穿过血管壁，从而使治疗直接进入血管外膜。该导管已用于人体先导研究，成功地通过外周递送导致药物在血管周围圆柱状沉积，创建了一个天然的药物洗脱储存库。我们现在建议将这项研究推进到人类临床试验中，具体目的是确认安全性，同时证明在外周动脉血管成形术时将雷帕霉素输送到外膜的积极生物学效应和临床益处。在这项提案中将开发的创新产品是一种将广泛适用于血管疾病的组合设备/药物疗法。我们认为，这项建议的意义在于：(A)我们正在解决顽固性的临床问题；(B)血管周围或外膜治疗可以作为几种常见的介入性血管重建术的辅助手段；(C)PAD的治疗成功可以迅速转化为冠状动脉和肾动脉再狭窄或冠状动脉和外周搭桥术后的再狭窄。如果这些第二阶段研究成功，我们打算进入关键的临床试验，并最终寻求FDA批准一种新的组合产品。