NV1FGF Fails in Phase 3 Trial of Angiogenesis Therapy for CLI

May 30, 2011—The Lancet announced publication online ahead of print of the phase 3 TAMARIS trial by Prof. Jill Belch, MD, et al. The TAMARIS investigators found that administration of a novel gene therapy, fibroblast growth factor type 1 (NV1FGF), which had shown promising results in a recent phase 2 trial to enhance the growth of new blood vessels in people with critical limb ischemia (CLI), does not reduce amputation or death. Sanofi-Aventis (Bridgewater, NJ) sponsored and directed the TAMARIS trial.

According to The Lancet, the publication highlights the challenges of finding an effective treatment for CLI. The Lancet noted that as the most severe form of peripheral artery disease, CLI affects one in ten adults > 50 years of age in high-income countries and annually results in > 150,000 amputations in the United States. CLI treatment is currently limited to surgical bypass or revascularization to improve blood flow and prevent amputation. However, these procedures are costly, and up to 50% of patients require subsequent surgery for wound complications, 20% need an amputation within 3 to 5 years, and many patients are unsuitable for such procedures. The lack of treatment options has led to extensive research into the development of therapeutic angiogenesis to reduce the need for amputations, although its long-term effects are not known.
 


In the phase 2 TALISMAN trial, nonviral DNA delivery of NV1FGF was well tolerated and showed a large reduction in amputations and a trend toward reduced death rates.

To provide further evidence, the phase 3 TAMARIS trial recruited 525 patients unsuitable for revascularization from 171 hospitals across 30 countries and randomly assigned them to intramuscular injections of NV1FGF (259 patients) or placebo (266). The investigators found that after 1 year, no difference in time to major amputation or death was recorded between the groups.

“TAMARIS provided no evidence that NV1FGF is effective in reduction of amputation or death,” the investigators commented. “Thus, this group of patients remains a major therapeutic challenge for the clinician.”
 
The investigators concluded, “[These results] portray the challenges faced by the development programs of single genes, such as extrapolation from conclusive animal studies to define optimum dose, vector, route, and duration of administration, as well as whether the administration of any one gene could result in therapeutic angiogenesis leading to the prevention of limb amputations.”


Accompanying commentary in The Lancet by Prof. F. Gerald F. Fowkes, FRCPE, and Jacqueline F. Price, MD, noted that trials of gene therapy in CLI are prone to difficulties. “Patients usually have widespread cardiovascular disease, and angiogenesis might be inhibited by risk factors, such as dyslipidemia and diabetes,” they stated. “In TAMARIS, 60.4% of patients had hyperlipidemia and 53.3% had diabetes, although no difference in effect was noted in those without diabetes. Cardiovascular drugs, such as statins (62.5% of patients in TAMARIS) and angiotensin-converting enzyme inhibitors (51.4%), might also have inhibited angiogenesis. Furthermore, many experiments suggesting efficacy are in young healthy animals, whereas patients are elderly with extensive disease and in whom gene therapy might be ineffective.”