CHICAGO – Gene therapy proved ineffective in critical limb ischemia patients with ischemic skin lesions unsuitable for revascularization in the largest-ever clinical trial of gene therapy for this application.
Results of the phase III, randomized, double-blind, 525-patient TAMARIS study showed a 37% rate of death or major amputation at 1 year in recipients of the gene controlling for the expression of angiogenic fibroblast growth factor 1, compared with a 33% rate in placebo-treated controls.
"This was a definitively negative trial," Dr. William R. Hiatt declared in presenting the TAMARIS results at the annual scientific sessions of the American Heart Association.
The TAMARIS findings are particularly disappointing in light of the earlier, highly impressive results of the phase II TALISMAN study. In that 125-patient study, the same gene delivery system, known as NV1FGF, resulted in a 56% reduction in the combined end point of death or major amputation at 1 year, said Dr. Hiatt, professor of medicine and cardiology at the University of Colorado, Denver.
The delivered gene, FGF1, codes for heparin-binding growth factor 1, which is a known angiogenic factor.
"I would merely say that this confirms the importance of large, well-conducted, randomized controlled trials. You really shouldn’t make therapeutic decisions based on phase II trials," he said.
Gene therapy recipients received four 4-mg intramuscular injections of NV1FGF over a 6-week period.
Dr. Hiatt said the concept of therapeutic angiogenesis "remains alive," but the focus should shift to stem cell–based therapies, which show great promise.
Indeed, elsewhere at the meeting Dr. Douglas W. Losordo presented the results of a phase II study of autologous CD34+ cells for critical limb ischemia unsuitable for surgical or percutaneous revascularization. In that 28-patient study, cell therapy recipients had a 74% greater amputation-free survival rate at 1 year than did placebo-treated controls.
Dr. Losordo, the designated discussant for the TAMARIS trial, said one possible explanation for the divergent results relative to the earlier phase II TALISMAN study is that TAMARIS was conducted in 30 countries on multiple continents, whereas TALISMAN was carried out in a more genetically homogeneous European population. It’s possible, he theorized, that there are genetic differences in critical limb ischemia and in the response to gene therapy.
New treatments for critical limb ischemia with tissue loss are desperately needed. There are 100,000 amputations per year in the United States for this condition. The amputation rate hasn’t changed in 3 decades, noted Dr. Losordo, professor of medicine and director of the Feinberg Cardiovascular Research Institute at Northwestern University, Chicago.
Dr. Hiatt disclosed that he has received a research grant from Sanofi-Aventis, which funded the TAMARIS trial. The CD34+ cell therapy study was sponsored by Baxter Healthcare. Dr. Losordo declared that he was previously a paid consultant to Baxter.