Although earlier trials were promising, the TAMARIS trial showed that an experimental gene therapy growth factor failed to prevent death or amputations in patients with severely blocked lower limb blood vessels. Sigrid Nikol, Asklepios Klinik St Georg, Hamburg, Germany, explains to VascularNews.com the negative results of TAMARIS.
What are the key learnings from the TAMARIS study?
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. The results of the phase III study do not confirm the phase II study findings and highlights the complexity of the development of innovative biological compounds like NV1FGF in a challenging disease such as critical limb ischemia. Despite recent advances in surgical and vascular techniques, a large number of patients suffering from this disease are not eligible for revascularization procedures and face amputation as their ultimate treatment option.
TAMARIS study is the largest clinical trial for the investigation of a pro-angiogenic therapy for critical limb ischaemia. The clinical trial programme for NV1FGF provided scientific background on this innovative biological compound and new global epidemiology data to help further the understanding of this rare but serious disease.
More than 520 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 intramuscular which lead to local expression of FGF1 in muscle cells of critical limb ischaemia patients which promotes local angiogenesis by stimulating cell migration and cell growth and 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).
How do you explain the negative TAMARIS results?
TAMARIS results did not confirm the preliminary efficacy findings that were observed in the phase II findings. These results confirm the importance of conducting large phase III studies with innovative biological compounds like NV1FGF, particularly in a complex disease like critical limb ischemia where, despite recent advances in surgical and vascular techniques, a large number of patients are not eligible for revascularisation procedures and face amputation as their ultimate treatment option.
Were the endpoints appropriate?
Yes, amputation free survival is a “hard endpoint”, clinically meaningful in this disease (and is also an endpoint required by regulators). An independent adjudication committee adjudicated amputations and confirmed that all major amputations in the trial were justified showing the robustness of the investigators judgment
Where there any differences in baseline characteristics between groups in the study?
There was no difference in baseline demographics between groups in the study (randomisation was stratified by country and diabetes status).
Was the trial conducted appropriately i.e. given the neutrality of effect, was the drug administered correctly etc?
The trial conduct was of high quality, subject to frequent quality checks, and the drug was administered appropriately and similarly in the two treatment groups.
Was the trial powered appropriately?
TAMARIS was well powered. The event rates (of major amputations and deaths) within the trial were as expected in the sample size assumptions, confirming that the trial was powered appropriately.
Why was TAMARIS conducted if TALISMAN did not meet the primary endpoint?
At the time TALISMAN was designed, ulcer healing was believed to be a strong clinical endpoint that could be appropriate to demonstrate the efficacy of NV1FGF. However, the outcomes of the secondary “hard” endpoints were unexpectedly conclusive for risk reduction of major amputation and death (-57%) and major amputation (-63%).
TAMARIS was thus designed to determine if these results could be replicated in a larger sample size.
How do you see stem cell therapy in the future in the treatment of peripheral arterial disease?
Stem cell therapy still has to prove any benefit. So far clinical trials were too small, had too short endpoints, were mostly uncontrolled and if controlled then they were either not randomised or not blinded.