Site-Specific Therapeutic Delivery

By David S. Cohen, Irvine California, June 22, 2019

A complete solution in the form of an adherent, unidirectional, completely biodegradable drug-eluting wrap.

The concept of site-specific therapeutic delivery, although conceptually attractive, has only been applied in vascular applications. Drug-eluting coronary artery stents are the most successful in terms of improvement of quality of life, and reduced morbidity and mortality. They provide an efficacious alternative to coronary artery bypass graft (CABG) surgery without the surgical trauma and complications. Moreover, in some patients whose grafts have lost function stents present a non-surgical reparative procedure. In peripheral arterial disease (PAD), drug-eluting stents, much larger, longer and carrying more drug, and drug-eluting vascular dilating (angioplasty) balloons are now being employed. However, these PAD devices overall efficacy have been called into question and, in some instances, recalled by the Food and Drug Administration (FDA) because of increased long-term mortality. The commonality of these local-drug delivery platforms is that they are designed only for ‘in-the-tube’ application thereby not applicable for unmet vascular needs requiring an ‘outside the tube’ treatment paradigm. NDSciences has such an ‘outside-the-tube’ solution in the form of an adherent, unidirectional, completely biodegradable drug-eluting wrap. This vascular wrap will deliver the drug paclitaxel. Paclitaxel is a potent inhibitor of cellular growth and proliferation and, as such, blocks the overgrowth of vascular smooth muscle cells. Vascular smooth muscle cell proliferation is the causative factor in the reduction and eventual blockage of blood leading to limb, organ and treatment failure. Critical Limb Ischemia (CLI), the most severe form of PAD, arterial-venous access failure in kidney hemodialysis patients, and occluded coronary artery bypass grafts are clear indications for a paclitaxel-eluting wrap (PEW).

The incidence of CLI, as the result of the Type 2 Diabetes Mellitus epidemic in the U.S., is growing rapidly. Treatment modalities are Tibial artery bypass graft surgery or amputation. However, within five years of graft surgery 65% of the patients will require amputation. Bare metal stents, drug-eluting stents, and drug-eluting balloons have not demonstrated efficacy in prolonging the time to or reducing the rate of amputation post-surgery. Placing a PEW around the grafted vessel at the time of surgery. Moreover, exposing the grafted vessel in the leg is a trivial procedure, thus reapplying a ‘new’ PEW can actually be a curative modality. Currently in the U.S. there are approximately 4 million CLI patients and this is projected to increase to 6 million by 2030. Currently, approximately $23 billion is spent on CLI patient care.

There are approximately 700,00 patients in the U.S. in end-stage kidney disease of which ~550,000 are undergoing hemodialysis. Due to the obesity and type 2 Diabetes Mellitus epidemic this population is increasing almost exponentially. Currently, there are only approximately 20,000 kidney transplants per year. In 2015, nearly $55 billion was spent on the care of dialysis patients; $40 billion derived from the Medicare fund and $15 billion from other local state and municipality sources (Medicaid, etc.). The routes to dialyze a patient are either PTFE (a Gore-Tex type material) arterial-venous access ports or arterial-venous fistulas. The access ports are prone to occlusion at 6-9 months following placement and following balloon dilation with or without stent placement the time of graft patency is even shorter. Fistulas, the now preferred dialysis route, are patent for one to two years following placement. However, 35% of fistulas fail to mature and become functional. There is no pharmacotherapy approved to prevent these occlusions. The occlusive process is similar to CLI and thus placement of a PEW at the time of graft or fistula placement can prolong patency. In the case of grafts, when a blocked graft is re-canalized with a balloon catheter, a PEW can be placed at the time of procedure. Hemodialysis patients have a high degree of morbidity and mortality. At five years following the onset of dialysis there is a 65% mortality. The goal of the PEW is to prolong graft or fistula patency allowing the patient more time in which to receive a transplant. The primary cause of death in these patients is essentially due to no longer having dialyzable sites.

CABG surgery has been performed for almost forty years to repair partially and fully occluded coronary arteries. The primary source of the graft is the saphenous vein taken from the leg. Within the last decade, the mammary artery has been used. Saphenous vein grafts, primarily because thin walled venous tissue is now being asked to assume the role of contractile, thick walled arterial tissue, have a 20% occlusion rate at one year. Mammary arteries, being an artery, have 9% occlusion rates at one year. The use of mammary arteries is limited because there is not much tissue available. Consequently, bypass procedures on multiple vessels are a hybrid of both saphenous vein and mammary artery grafts. There is no treatment to prevent occlusion and once a blockage occurs it is corrected either by stents or repeat CABG surgery. Hence, anything that can prevent occlusion and be employed at the time of surgery will create a market unto itself. Consequently, a PEW can become the only treatment of choice.

CLI, arterial-venous access, and as an adjunct to CABG surgery are not the only potential platforms for the drug-eluting wrap platform. A wrap can be used in oncology indications as a solid tumor or as a cancer stem-cell core wrap delivering drugs, antibodies, and gene products. In erectile dysfunction, a wrap delivering nitrates to the penis can demonstrate efficacy, especially in patients with systemic circulatory dysfunction and Para- or quadriplegic men. As a drug-eluting sheath, prior to becoming a wrap, this platform can be an adjunct to multiple surgical procedures as a preventative to scarring and blocking the formation of surgical adhesions. The potential uses for this therapeutic delivering platform are far-reaching limited only by the users imagination.