Image source: Spectranetics

CHICAGO—NV1FGF 4 gene therapy did not prevent amputations or death among patients with critical limb ischemia (CLI) who were unsuitable for revascularization, based on the late-breaking TAMARIS phase III trial, presented today at the American Heart Association (AHA) Scientific Sessions.

As a study discussant in this morning's press conference, Douglas W. Losordo, MD, from the Program in Cardiovascular Regenerative Medicine at Northwestern Memorial Hospital in Chicago, spoke to the difficult nature of CLI.

“Within the first year of diagnosis, 20 percent of patients die, and an additional 25 to 30 percent require an amputation. In the last three decades in the U.S., amputation rates for patients with critical limb ischemia have not changed, signaling a need to develop novel strategies for these patients,” he said.

Local gene therapy using non-viral plasmid DNA encoding acidic fibroblast growth factor (referminogene pecaplasmid, also known as NV1FGF) demonstrated positive phase 2 results on both amputation and mortality in CLI. The TAMARIS phase III trial tested the hypothesis that an intramuscular injection of NV1FGF would confirm the benefit on amputation-free survival in CLI.

Slideshow | NV1FGF Gene Therapy on Amputation-Free Survival in Critical Limb Ischemia - Place 3 Randomized Souble-Blind Placebo-Controlled Trial

William R. Hiatt, Iris Baumgartner, Sigrid Nikol, Eric Van Belle, Vickie Driver, Lars Norgren, Jill Belch (TAMARIS steering committee)

TAMARIS enrolled 525 CLI patients (523 treated), who were unsuitable for revascularization and had stable ischemia skin lesions, at 170 sites in 30 countries. The researchers randomized patients double-blind to receive eight intramuscular injections on the same leg of either 2.5 ml NV1FGF at 0.2 mg/ml or placebo on days one, 15, 29 and 43. The primary endpoint was the reduction of major amputation or death, whichever came first, at one year.

Of patients on placebo, 21 percent suffered a major amputation during the trial, compared to 26 percent of those on the gene therapy regimen. Fifteen percent of the placebo group died, compared with 18 percent of the gene therapy group. Neither of these findings represent a statistical significance.

“The results were consistent among regions, by diabetes and other relevant subgroup analysis,” said study investigator William R. Hiatt, MD, professor of cardiology at the University of Colorado School of Medicine in Aurora, who presented the study at this morning’s press conference.

“Overall, it’s a very disappointing result. It’s troublesome after having a quite remarkable phase II trial,” Hiatt said. He said that the difference between phase II TALISMAN and phase III TAMARIS outcomes may be explained by “a chance finding,” and confirms the importance of large, well-conducted randomized, controlled trials.

Losordo told Cardiovascular Business News that the expansion process from a phase II trial, which was concentrated in Europe, to a phase III trial with additional sites in Eastern Europe, South America and Asia may have had an effect on the outcomes as well. “It’s possible that the demographics and the genetics of the disease, or the response to the therapeutic could have been altered,” Losordo said. “However, these TAMARIS data will be further investigated in hopes of uncovering a more concrete understanding.

“Cell-based therapies might hold the most promise in the future,” said Hiatt. “Specifically, the concept of angiogenesis is alive, but in TAMARIS, gene therapy did not prove effective.”

Sanofi-Aventis funded the trial.