Below the Knee Restenosiss

Scope of the Problem

With a prevalence of approximately 27 million people in Europe and North America, peripheral artery disease (PAD) is a critical public health issue. Due to worldwide demographic changes towards an older population, the prevalence of PAD is likely to increase dramatically over the next 20 years.

The term PAD is used to refer to the obstruction of blood flow in the arteries, but does not include coronary or intracranial vessels. PAD can result from atherosclerosis, embolism, thrombus formation or inflammatory processes leading to arterial stenosis or blockage. PAD is a major healthcare issue worldwide and patients with PAD have an increased risk of mortality, myocardial infarction and cerebrovascular disease. The predicted increase in the prevalence of PAD will intensify the demands placed on the healthcare services around the globe.

PAD therapies can include vessel bypass surgery or endovascular intervention: minimally invasive, catheter-based procedures that push or cut plaque out of the way so that normal blood flow can resume. Unfortunately, these endovascular procedures are plagued by inflammation and injury that leads to a buildup of new tissue similar to scar tissue. This can lead to re-obstruction, or restenosis, of the vessel. Local drug therapy has been shown valuable in the endovascular treatment of PAD with drug-eluting stents, drug-coated balloons, and the adventitial micro-infusion of drugs with the Bullfrog® device.

Advantage of Needle-Based Delivery

For years, conventional wisdom stated that neointimal hyperplasia was a phenomenon governed by tissue reaction from the inner vessel layers (the intima and media). It is now known that the adventitial inflammatory process recruits cells and leads to proliferation and migration of fibroblasts from the adventitia, through the media and into the intima, where these cells contribute to neointimal volume and vessel narrowing. These data highlight the biological relevance of the adventitia, which is perhaps best targeted through the use of direct adventitial or perivascular therapies.

The perivascular “outside-in” approach to drug delivery has distinct advantages over the “inside-out” approach exemplified by endovascular drug elution and other local delivery systems. In particular, the perivascular approach leads to

1. Cylindrical (longitudinal and circumferential) distribution of drug around a vascular lesion from a single point infusion site through the vessel wall, and

2. Transmural distribution with high adventitial concentration and tapering concentration toward the luminal endothelial layer.

Perivascular or adventitial application of therapeutic agents leads to more effective inhibition of adverse vascular remodeling; while minimizing toxicity to the endothelium and promoting greater re-endothelialization, as compared with endovascular drug delivery.

Phase 2 Clinical Data

The TANGO Phase 2 trial was a prospective, multi-center, randomized dose escalation study to document the effects of adventitial delivery of temsirolimus (n=40) versus adventitial delivery of sham saline (n=20) after revascularization of lesions below the knee in symptomatic patients with severe claudication (Rutherford 3) or critical limb ischemia (CLI, Rutherford 4-5). Subjects were followed up for 12 months post-index procedure.

The principal analysis on the 53 per protocol (PP) patients in the TANGO trial revealed superior primary efficacy of the treatment arm, with absolute reduction in the absolute rate of clinically relevant target lesion failure reduced by 27.1% at 6 months. Subgroup analysis of all TASC B-D lesions (N=36) revealed absolute rate of clinically relevant target lesion failure reduced by 39.2%. Freedom from 30-day major adverse limb event or peri-operative death was 100% in all groups.