Improved Adventitial Rapamycin Therapy for Peripheral Artery Restenosis

描述（由申请人提供）：外周动脉疾病（PAD）影响900万至1200万美国人，每年有150万人需要干预（407,400人接受搭桥或截肢；1,080,000人接受血管成形术、支架或动脉粥样硬化切除术）。不幸的是，只有三分之一的患者在股动脉球囊成形术一年后动脉通畅。裸金属支架[5-7]消除了弹性反冲和限流夹层，但没有显著影响内膜增生引起的再狭窄[3,8 -10]。事实上，放置在股腘段的支架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并不比裸支架好[13-15]。最近，在外周动脉中使用药物包被球囊已显示出改善血管通畅的潜力，而无需植入支架。然而，基于光的治疗（药物洗脱球囊和支架）的动力学将药物的最大浓度置于光壁界面。这明显的缺点是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着关键作用，有助于新内膜细胞体积和不良重塑。我们已经成功完成了第一阶段研究的目标，在临床前研究中，我们已经证明了无毒，有效剂量的雷帕霉素，一种著名的抗再狭窄药物，采用新型纳米颗粒配方，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，并在外膜中产生高浓度，在管腔表面产生较低浓度。墨卡托医疗系统公司开发了一种导管，当气球膨胀时，它可以滑动一根针穿过血管壁，从而可以直接治疗外膜。导管已用于人体初步研究，成功的体外输送导致药物在血管周围的圆柱形沉积，创造一个天然的药物洗脱库。我们现在提议将这项研究推进到人体临床试验，其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。在本提案中开发的创新产品是一种广泛适用于血管疾病的联合设备/药物治疗。我们认为，这一建议的意义在于：(a)我们正在解决一个难以解决的临床问题；(b)血管周围或血管外治疗可以作为几种常见介入血运重建技术的辅助手段；(c) PAD治疗的成功可以迅速转化为诸如冠状动脉和肾动脉再狭窄或冠状动脉和外周旁路移植术后再狭窄的情况。如果这些2期研究成功，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。

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.