Vein Graft Drug's Failure Shows Gaps in Knowledge

By Jeff Evans

WASHINGTON -- The failure of the drug edifoligide to improve the rate of vein graft failure in peripheral and coronary artery bypass patients illustrates the need for a greater understanding of the pathophysiology of vein graft disease, Michael S. Conte, M.D., said at a conference sponsored by the Society for Vascular Surgery.

Vein bypass grafts fail at a relatively alarming frequency within the first few years after their placement. Conventional drugs have had little clinical impact in preventing these failures, said Dr. Conte of the department of surgery, Harvard Medical School, Boston.

Vein bypass grafts appear to undergo one of three different kinds of failure: intimal hyperplasia or maladaptive remodeling, which causes most failures within the first 2 years; early graft occlusion, which develops in 5%-7% of grafts within the first 1-2 months and occurs as a result of technical failure, intrinsic problems with the graft, or extrinsic conditions, such as limited outflow or hypercoagulability; or atherosclerosis in the graft and in the inflow and outflow arteries.

"We think that we understand a little bit about [vein bypass graft failure] pathophysiology, based on different timing of graft failures but I'm not sure we really do quite yet."

Most researchers have targeted the development of therapies to the migration and proliferation of smooth muscle cells to the vein wall, which is thought to initiate the growth of intimal hyperplasia and the accumulation of lipids and fibrosis.

To regulate the cell cycle in smooth muscle cells, researchers from Corgentech Inc. synthesized a short double-stranded DNA "decoy" molecule that mimics the DNA sequence found in several cell-cycle genes that are regulated by a transcription factor called E2F.

In animal models of arterial injury and vein bypass grafting, E2F bound to the double-stranded DNA decoy molecule, named edifoligide, preventing the transcription factor from interacting with its normal target sequence in the chromosome of the cells and inhibited intimal hyperplasia of the vein graft after one treatment (J. Thorac. Cardiovasc. Surg. 2001;121:714-22).

Dr. Conte and his colleagues became involved in a series of human clinical trials testing edifoligide (PREVENT: Project in Ex-Vivo Vein Graft Engineering via Transfection), once a standardized device was developed that allowed greater than 80% uptake of edifoligide by cells in the vein wall of a graft after 10 minutes.

In the phase I, or PREVENT I, trial, 33 patients who were undergoing lower-extremity bypass with an autologous vein received grafts treated with either edifoligide or saline. The randomized, double-blind trial showed that about 90% of the cells in small segments of the vein treated with edifoligide took in the decoy molecule. Edifoligide also inhibited specific cell-cycle genes and reduced the proliferation of smooth muscle cells in the graft (Lancet 1999;354:1493-8).

The drug continued to show potential in PREVENT II, a double-blind, randomized, phase II study of 200 patients who were undergoing a cardiac artery bypass graft. Grafts treated with edifoligide had a 30% lower rate of vessel lumen occlusion of 75% or more, compared with those treated with saline, according to results from coronary angiography. In intravascular ultrasound images, total wall volume of the grafts treated with edifoligide declined by a significant 30%, compared with those that received saline.

Based on the results of those trials and the significant unmet clinical need, the Food and Drug Administration gave a fast-track designation for phase III trials to test edifoligide for the prevention of vein graft failure, Dr. Conte said.

But according to recent statements issued by Corgentech, edifoligide failed to show any benefit for primary and secondary end points in two phase III trials.

In the PREVENT III trial of 1,404 patients with critical limb ischemia who needed peripheral artery bypass graft surgery, there was no difference between edifoligide and placebo on the primary end point of limb amputation. No differences were seen in secondary end points of critical graft stenosis, recurrent limb ischemia, or quality of life.

Similar results were reported in the PREVENT IV trial, which tested edifoligide against placebo in 3,014 patients for the prevention of vein graft failure after coronary artery bypass surgery.

Dr. Conte gave several possible reasons for the negative results. Multiple isoforms of E2F exist, and the drug may not have inhibited them all. Edifoligide's pharmacokinetics may not have allowed it to inhibit E2F adequately. And the pathophysiology of coronary and peripheral vein graft failure may not be the same, he said.

Corgentech does not plan to develop edifoligide further.