Edifoligide no better than placebo for clogged veins

A new drug, edifoligide, designed to prevent the clogging of veins used in coronary bypass surgery was no more effective than a placebo, according to the results of a Phase III clinical trial led by researchers at Duke Clinical Research Institute (DCRI).

In a coronary artery bypass procedure, surgeons typically remove portions of the saphenous vein from patients' legs and use them as conduits to reroute blood around a blockage in arteries supplying blood to the heart. The most common reason for subsequent failure of the grafts is the progressive narrowing of the vein, which is largely the result of a process known as neointimal hyperplasia.

Since veins are structurally different from arteries, the increased pressure and stress on the implanted vein causes proliferation of smooth muscle within the vessel. Edifoligide, an E2F transcription factor inhibitor, showed an ability in earlier studies to block this cellular proliferation.

"The results of our Phase III trial showed that the edifoligide was absolutely neutral in all endpoints when compared to placebo," said Duke cardiologist John Alexander, M.D., who presented the results of the trial Nov. 13, 2005, at the annual scientific sessions of the American Heart Association. The results of the trial are also being published early and online by the Journal of the American Medical Association.

"Failure of at least one vein graft is quite common within a year of bypass surgery" Alexander said. "While edifoligide had no effect in preventing neointimal hyperplasia, longer-term follow-up and additional research is needed to determine whether the drug has longer-term beneficial effects and to better understand the mechanisms and consequences of vein graft failure."

In response to shear forces and increased pressures in the vein, cells growth increases in the inner lining of the vein. These cells secrete a variety of proteins known as cytokines that modulate the immune response. These cytokines cause inflammation that intensifies the process of atherosclerosis in the newly formed tissue. The family of E2F transcription factors has been implicated in "turning on" many of the genes responsible for this process.

The drug edifoligide is an oligonucleotide "decoy" or short fragment of DNA, that is structurally similar to the E2F transcription factor binding site, and thereby blocks E2F transcription factor binding and subsequent gene activation. The drug appeared to be promising in animal models and two small clinical trials involving 41 and 200 patients, said the researchers.

The latest randomized, double-blind trial, known as PREVENT-IV, enrolled 3,014 patients at 107 U.S. sites who underwent coronary artery bypass graft procedures involving at least two vein grafts. Half of the patients had their leg veins pressure-treated with the drug for ten minutes prior to implantation, while the veins of control patients were treated in the same way, but with a placebo. The average number of veins grafted was about 2.5 per patient.

The primary endpoint measured by researchers was how many patients had at least one vein graft more than 75 percent blocked more than a year after surgery.

The researchers found that 45.2 percent of patients with treated veins had at least one vein more than 75 percent blocked, compared to 46.3 percent for the control group. In terms of total veins, 28.5 percent of treated veins were more than 75 percent occluded, compared to 29.7 percent in the control group. The differences were not clinically or statistically significant, said the researchers.

There was also no difference between the two groups in terms of clinical events, they said. In the treated group, 7.6 percent of patients experienced death, heart attack or need for another procedure, compared to 9.1 percent for the control group.

The results of the trial were similar to that of PREVENT III, which tested the drug in patients who underwent peripheral artery bypass surgery.

"Given the results we've seen in the latest two large clinical trials (PREVENT III and IV), the earlier promising results with edifoligide were probably due to its small sample size, less complete follow-up, or chance," Alexander said.

The DCRI is currently leading a Phase I/II pilot trial (PREVENT V), which is assessing the effectiveness of edifoligide in preventing neointimal hyperplasia in vascular access grafts in patients undergoing dialysis for kidney failure.

While the results of PREVENT IV were largely negative, Alexander said that researchers gained insights. For example, the process developed to infuse the drug into the vein tissue could be used in other surgical settings where a drug needs to be delivered to a single site instead of systemically.