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Biologic Therapies for Patients with Critical Limb Ischemia
Critical limb ischemia (CLI) represents the most severe degree of peripheral arterial disease (PAD) manifesting by either ischemic rest pain or tissue loss. In patients with CLI who do not have revascularization options, major amputation is required within 1 year in as many as 40% of patients, and mortality is as high as 20%. Biologic therapies, including gene therapy and cellular therapy, offer the potential to promote wound healing and prevent amputation in patients who otherwise have no options for revascularization.
Therapeutic angiogenesis is defined as the growth of new blood vessels from preexisting blood vessels in response to growth factor stimulation. This has been shown to occur in animal models of hind limb ischemia and can be induced by angiogenic proteins such as vascular endothelial growth factor (VEGF) or by cellular therapy using stem cells or bone marrow aspirate. The concept of angiogenesis was introduced into the clinical realm by Jeffery Isner in the early 1990s. Various growth factors such as VEGF, hepatocyte growth factor (HGF), and fibroblast growth factor (FGF) have been shown to promote angiogenesis in animal models.
Because of the short half-life of these proteins, gene therapy has been used to maintain sustained expression in the ischemic limb. Most clinical trials to date have used intramuscular injection of either a gene or cellular therapy. In the case of gene therapy, expression of the protein is maintained from 2 to 6 weeks. General concerns regarding angiogenic therapy safety have been related to the potential for off-target angiogenesis that could result in promotion of occult tumor growth or accelerated progression of diabetic proliferative retinopathy. To date, these concerns have not occurred in angiogenic clinical therapy trials.
Gene Therapy Trials
FGF has been extensively studied in the context of CLI. The TALISMAN phase II trial ( Clinicaltrials.gov NCT00798005 ) enrolled 125 patients and reported a significant improvement in amputation-free survival of 52% in placebo-treated patients with no options for revascularization compared to 73% in patients treated with FGF plasmid ( p = .009). In a separate study, these investigators showed proof of concept of gene therapy when they identified the FGF plasmid, mRNA, and protein in the affected extremities of patients with CLI who received FGF plasmid injections before amputation.
These findings led to completing a phase III pivotal trial, the TAMARIS trial ( NCT00566657 ). Unlike the earlier phase II trial, the TAMARIS trial failed to show a difference in amputation-free survival when compared to placebo in patients with CLI ( Table 1 ). This trial enrolled 525 patients at 170 sites in more than 30 countries. Subjects had either a hemodynamically confirmed ischemic ulcer or minor gangrene. Major amputation or death at 1 year occurred in 33% of placebo-treated patients and 36% of treated patients. The amputation-free survival for both groups was similar to that for the FGF-treated patients in the phase II TALISMAN trial. The likely explanation for the different results observed in the phase II TALISMAN and phase III TAMARIS trials is a type II error.
TABLE 1
TAMARIS Trial: NV1FGF Plasmid versus Placebo (525 Patients)
| 12-Month Endpoint | NV1FGF (%) | Placebo (%) | p Value |
|---|---|---|---|
| Amputation-free survival | 63 | 67 | .48 |
| Amputation | 26 | 21 | .31 |
| Death | 18 | 15 | .53 |
Several clinical trials have evaluated hepatocyte growth factor (HGF) plasmid in treatment of patients with CLI and no option for revascularization. Early phase II trials ( NCT00189540 , NCT00060892 ) have shown that HGF plasmid gene therapy can improve transcutaneous partial pressure of oxygen (TcP o 2 ) and pain scores in patients with CLI compared to placebo. A simultaneous trial in Japan was stopped early by the data safety monitoring board owing to an improvement in ulcer size in 100% of the HGF plasmid–treated patients compared to an improvement in 40% of the placebo-treated patients ( p = .014).
There are currently no FDA-approved gene therapies to treat patients with CLI.
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