TAMARIS: Gene Therapy Fails in Phase 3 Trial of Critical Limb Ischemia

November 17, 2010

November 17, 2010 (Chicago, Illinois) — The largest gene-therapy trial ever in critical limb ischemia has failed to show a significant benefit of this approach in these very sick patients. The randomized, double-blind, placebo-controlled phase 3 trial, called TAMARIS, tested the concept of therapeutic angiogenesis via the transfer of a gene encoding human fibroblast growth factor (FGF-1) in patients with end-stage unreconstructible lower-extremity ischemia who face a very high likelihood of limb amputation or death.

Dr William R Hiatt

This study was driven by a "strikingly positive phase 2 trial, which showed a significant reduction in the risk of amputation or death, by 50%," with this approach, said Dr William R Hiatt (University of Colorado, Denver), who presented the findings during a late-breaking clinical-trial session at the American Heart Association 2010 Scientific Sessions today. But Hiatt said the new TAMARIS result "was definitely negative" and "underscores the need to do properly conducted phase 3 trials," even when phase 2 studies appear encouraging.

Discussant of the trial, Dr Douglas W Losordo (Northwestern Memorial Hospital, Chicago), said the TAMARIS trial was "challenging, a tough venture in these very sick patients," but it was nevertheless "scrupulously conducted."

Dr Douglas W Losordo

Both Losordo and Hiatt said the amputation and mortality rates seen in the phase 3 trial were lower, at around 30%, than those seen in the phase 2 study, at around 50%, so the positive phase 2 results "are likely the play of chance," because there were no differences in patient characteristics and event rates between the different geographic regions in TAMARIS. "The phase 3 trial definitively answers the question," Hiatt noted.

Chair of the press conference where the results were presented, Dr Elliot Antman (Brigham and Women's Hospital, Boston), observed: "Even if the results are negative, they are important because they inform our practice."

Hiatt agreed. He added that this was not the end of the road for gene- and cell-based therapies in critical limb ischemia; a number of companies are still developing such approaches. "But we still have a lot to learn," he commented.

No Differences in Any of the End Points, But Therapy Seems Safe

The fate of patients with critical limb ischemia is grim: around 20% will die in the first year after diagnosis, 35% will be alive but will have undergone amputation, with the remaining 45% alive without amputation. Despite the use of revascularization or bypass in the affected limb, "the amputation rates have not changed in the past three decades in the US," Losordo explained. The concept behind the gene therapy is the delivery of a gene that will encode for a growth factor, which, it is hoped, will stimulate the development of new blood vessels and improve the limb ischemia.

TAMARIS was conducted in 525 critical-limb-ischemia patients in 171 sites in 30 countries in North and South America, Europe, Asia, and South Africa. Patients were randomized to four intramuscular injections of a nonviral plasmid containing a gene encoding FGF-1 4 mg or placebo into the affected limb every two weeks; they were assessed at one year for efficacy and safety, with a three-year follow-up planned for safety.

The primary end point was the first occurrence of major amputation (above the ankle) of the treated leg or death from any cause over 12 months. Secondary end points were all amputations, death, ulcer healing, pain relief, and functional status.

There was no difference between the active FGF arm and placebo in the primary end point: there were 96 major amputations or deaths (37%) in the FGF group vs 86 (33%) in the placebo group (p=0.48). There were no differences in any secondary end points between the two treatment groups either, including major amputation (p=0.31) and death (p=0.53).

The treatment appeared safe, however, with no safety signals at one year, and longer follow-up of this end point is planned.

The results were consistent among regions and by diabetes status, as well as other relevant subgroup analyses.

"The concept of angiogenesis is alive, but the way we gave this particular gene product was not associated with positive results," Hiatt concluded.

TAMARIS was sponsored by Sanofi-Aventis. Hiatt has received grants/research support from Sanofi-Aventis. Losordo is involved with studies of similar products from Baxter Healthcare and was previously a paid consultant to Baxter.


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