For angiogenic gene therapy, mixed results in phase I/II trials were followed by a negative result in a very large phase III trial (TAMARIS), Sigrid Nikol, Asklepios Klinik St Georg, Hamburg, Germany, will tell delegates at CX 33. “This demonstrates that large placebo-controlled randomised trials are a prerequisite to exclude statistical errors before a novel therapy can be established and widely distributed,” she told Vascular News.
Nikol will take the audience through the stem cells trials conducted so far and show what we have learned in the treatment of peripheral arterial disease. “Stem cell therapy still has to prove any benefit in the treatment of peripheral arterial disease. Until today published clinical trials were too small, had too short follow-up periods, in some cases unsuitable endpoints, were mostly uncontrolled and if they were controlled, then they were either not randomised or not blinded. The large number of published pilot trials may suggest beneficial effects, yet, we are still far from an established new therapy,” she said.
Results of the TAMARIS trial
The results of the phase III TAMARIS trial evaluating the investigational angiogenic therapy NV1FGF (riferminogen pecaplasmid) were presented at the American Heart Association Scientific Sessions in November 2010. The results of the study did not confirm the phase II findings and highlighted the complexity of the development of innovative biological compounds like NV1FGF in a challenging disease such as critical limb ischaemia. “Despite recent advances in surgical and vascular techniques, a large number of patients suffering from this disease are not eligible for revascularisation procedures and face amputation as their ultimate treatment option,” Nikol said.
Five hundred and twenty six patients from 30 countries with critical limb ischaemia and skin lesions, unsuitable for standard revascularisation, were included in the TAMARIS trial. Disease characteristics are similar by geographic region. In addition, when patients reach the end stage disease, there does not seem to be a difference between patients with diabetes or without, with regards to the vascular disease.
The mechanism of action for NV1FGF was proven in a phase I clinical trial where NV1FGF was administered intramuscularly – which leads to local expression of FGF1 in muscle cells of critical limb ischaemia patients and promotes local angiogenesis by stimulating cell migration and cell growth. It appears to induce the formation of new blood vessel networks (PM105 study, reference Baumgartner, 2009). The TAMARIS trial hypothesis was that, local expression of the angiogenic growth factor FGF1 will translate into a meaningful clinical benefit, such as prevention of amputation in critical limb ischaemia patients. This hypothesis was based on a positive phase II finding (63% reduction of major amputation on the secondary endpoint of TALISMAN study).
“The outcome of published trials using peripheral and bone marrow cells will be reviewed. Most of these trials published to date are level 4 trials; few are level 1b or level 2 trials,” Nikol said.