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DENVER -- Hepatocyte growth factor plasmid gene therapy for patients with lower extremity critical limb ischemia is headed for a pivotal phase III clinical trial following two successful phase II studies.

At the Vascular Annual Meeting, Dr. Richard J. Powell presented the results of one of the phase II randomized trials, in which hepatocyte growth factor (HGF) plasmid gene therapy resulted in beneficial effects on limb perfusion, rest pain, and wound healing compared to placebo.

The gene therapy was delivered via intramuscular injections under duplex ultrasound guidance based upon a patient's individualized pattern of ?arteriographically defined occlusive disease, explained Dr. Powell, professor of surgery at Dartmouth-Hitchcock Medical Center, Hanover, N.H.

HGF is a master regulatory gene with multiple antiapoptotic, antifibrotic, and antiantiangiogenic effects. Among the key genes that HGF regulates are vascular endothelial growth factor and matrix metalloproteinases-1, -3, and -9. In an earlier dose-finding study, Dr. Powell and his coworkers demonstrated that HGF plasmid gene therapy increased transcutaneous oxygen tension in patients with critical limb ischemia (CLI) (Circulation 2008; 118:58-65).

The phase II study involved 27 patients with CLI. All had major tissue loss or gangrene and were noncandidates for all standard revascularization options. Twenty-one subjects were randomized to three sets of intramuscular injections of HGF plasmid gene therapy on days 0, 14, and 28. Each set consisted of eight 3-mL injections into the ischemic limb. Six patients received placebo injections.

Mean baseline ischemic wound size was 7.4 cm2. After 3 months of follow-up, one patient in the gene therapy group had achieved complete wound healing. After 6 months, there were four such patients and, after 1 year of follow-up, there were seven. In contrast, no one in the placebo arm experienced complete wound healing.

The toe brachial index deteriorated throughout follow-up in controls but showed a small increase over time in the gene therapy group. By 6 months, this difference achieved significance.

Pain scores on a 10-point visual analog scale remained relatively unchanged over time in the placebo group while showing progressive improvement in the HGF arm. By 6 months, pain scores were an average of 2.5 points lower in the gene therapy group than in controls, a significant difference.

However, there were no differences between the two treatment arms in terms of major amputation rate--20% with placebo, 19% with gene therapy--nor in mortality, which was 13% in controls and 19% with HGF therapy.

A Japanese phase II trial was recently halted early for ethical reasons because of the significant benefits documented in the HGF plasmid gene therapy arm, Dr. Powell noted.

Then Society for Vascular Surgery President G. Patrick Clagett congratulated Dr. Powell for including in his study more representative "real-world" no-option patients with CLI. "One of my frustrations with clinical trials of these types of therapies has been that they're very selective and have included only patients with ulceration. That's quite a rare patient in my experience; I usually get patients with amputations that won't heal or with major gangrene," commented Dr. Clagett, professor of surgery at University of Texas Southwestern Medical Center at Dallas.

Dr. Powell disclosed that he serves as a consultant to Anges Inc., which is developing HGF plasmid gene therapy.