Wednesday, April 6, 2005

PREVENT IV Results Announced
By Julie McKeel

Corgentech, Inc. announced in a March 30 press release that treatment with edifoligide (E2F Decoy) failed to meet the PREVENT IV trial's primary and secondary endpoints. Although the PREVENT III trial results released on December 6, 2004 did not meet the trial's endpoint goals, PREVENT IV activities continued at a rigorous pace as it could not be assumed that the PREVENT III results predicted failure for the PREVENT IV trial.

PREVENT IV was a multi-center, placebo-controlled, double-blind, randomized Phase 3 study that was conducted in collaboration with The Society of Thoracic Surgeons (STS), the Duke Clinical Research Institute, and Corgentech, Inc. The DCRI's Dr. John Alexander, Dr. Robert Harrington, and Dr. Eric Peterson coordinated this collaboration.

The PREVENT Trials (I, II, III, IV and V) were designed to evaluate the use of edifoligide (E2F Decoy) to prevent graft failure. PREVENT I, II and V were Phase II safety and feasibility trials. PREVENT III and IV were pivotal Phase III studies designed to support U.S. Food and Drug Administration (FDA) approval of edifoligide.

According to the PREVENT IV steering committee co-chairs, Dr. Nicholas Kouchoukos and DCRI Director Dr. Rob Califf, much will be learned from PREVENT IV about the management and outcomes of patients undergoing coronary artery bypass surgery. "We are obviously disappointed that edifoligide did not result in a significant reduction in the incidence of coronary artery bypass graft failure between 12 and 18 months," Kouchoukos and Califf stated in their letter to the site coordinators. "However, we are also proud of what you have accomplished over the last 3 years. Thanks to all of your efforts, PREVENT IV will be remembered as a highly successful cardiac surgical trial with a remarkable angiographic follow up rate."

PREVENT III assessed edifoligide's ability to prevent the clinical complications of vein graft failure in peripheral vascular disease patients undergoing bypass procedures. The DCRI's Clinical Events Classification (CEC) group confirmed (adjudicated) the endpoints for the PREVENT III trial and Duke faculty served on the Data Safety and Monitoring board.

PREVENT IV trial work at DCRI began nearly 3 years ago. PREVENT IV enrolled 3,014 patients undergoing CABG surgery at over 100 U.S. centers. The primary endpoint was the percent reduction in the incidence of vein graft failure between the E2F Decoy treated and placebo groups.

In the trial, vein graft failure was defined as Core Lab read blockage of the graft of 75 percent or greater as measured by coronary angiography at 12 months. Safety was assessed by monitoring adverse events, post-operative complications and laboratory abnormalities. PREVENT IV's confirmatory clinical endpoint is 5-year major adverse cardiac events (MACE). The DCRI's follow-up group is collecting the 5-year data through direct patient contact; the CEC is adjudicating (confirming) myocardial infarction and vein graft failure with revascularization.

PREVENT V is a phase 1/2 pilot trial designed to assess edifoligide's ability to prevent narrowing of the vascular access grafts placed in patients with chronic renal failure requiring hemodialysis. DCRI is performing project and data management, safety surveillance, and statistical activities.

The E2F decoy was "fast tracked" by the FDA. In an unusual move, the FDA was allowing submission of a "surrogate" primary efficacy endpoint of PREVENT IV — angiographic data at 1 year — while clinical data was still being collected (through 5 years).

In PREVENT IV, the DCRI's site management team worked with the STS to identify a group of approximately 100 U.S. sites that had the ability to recruit eligible patients and comply with the protocol requirements. In just 1 year, 3014 patients were enrolled. The first 2400 patients were scheduled to undergo 12-18 month angiography. PREVENT IV met its aggressive goal of 80% angiographic follow-up on February 18, 2005. Final data was submitted for analysis and the primary endpoint data was reported on March 29, 2005. The DCRI's statistics, clinical data integration, clinical events classification, safety surveillance and finance groups contributed significantly to the success of this project.

The PREVENT trials were sponsored by Corgentech Inc. and Bristol-Myers Squibb Company. The DCRI's Dr. John H. Alexander was the principal investigator and Diane Joseph provided the project leadership for this effort.

John Alexander, M.D.

Robert Harrington, M.D.

Eric Peterson, M.D.