Intramuscular injection of a gene therapy known as AMG0001 (Collategene, AnGes Inc.) significantly decreased healing time and increased healing rates of neuroischemic ulcers compared with placebo in patients with chronic limb-threatening ischemia (CLTI) and nonhealing ulcers associated with peripheral artery disease (PAD), a phase 2 trial showed. 

These patients face devastating risks for amputation and mortality in the absence of an FDA-approved therapy to directly promote wound healing, said study co-investigator David Armstrong, MD, distinguished professor of surgery and neurological surgery at the Keck School of Medicine of the University of Southern California, Los Angeles. 

Many of them “live in a therapeutic ‘gray zone’ of being too ischemic to heal, yet not candidates for surgical or endovascular intervention,” he told Medscape Medical News.

Prior clinical studies have demonstrated the safety of hepatocyte growth factor (HGF) plasmid delivered intramuscularly to patients with severe limb ischemia, Armstrong and colleagues noted. AMG0001, a plasmid encoding human HGF, was designed to promote ulcer healing in these patients. 

In the study known as LEGenD-1, recently published in Circulation: Cardiovascular Interventions, the researchers enrolled 75 adults with neuroischemic ulcers and toe pressure or transcutaneous oxygen pressure between 30 and 59 mmHg. Participants were randomized to 4-mg AMG0001 (n = 22), 8-mg AMG0001 (n = 27), or placebo (n = 26). The mean age of the participants was 62.6 years, 80% were male, and 71% had diabetes. The study’s two primary endpoints were the time to complete healing and the proportion of patients with healed ulcers after 6 months.

Overall, the median healing time was significantly shorter in patients treated with AMG0001 vs placebo (84 vs 280 days, P = .007). The median time to healing was significantly shorter with each dose than with placebo as well (98 days with 4 mg and 84 days with 8 mg). 

Additionally, significantly more patients treated with AMG0001 had healed at 6 months compared to placebo patients (63.3% vs 38.5%, P = .053). Healing rates remained significantly higher in the AMG0001 patients than in placebo patients at 12 months (77.6% vs 46.2%, P = .010). 

Safety data were similar across the groups, with low incidence of adverse events. A total of three deaths were reported during the study; two in the placebo group and one in the 8-mg AMG0001 group. 

Implications and Next Steps

The findings were strengthened by the placebo-controlled design, standardized wound care protocols, and blinded assessment of ulcer healing, the researchers noted. “The results suggest genuine biologic activity, not simply better wound care,” Armstrong told Medscape Medical News.

“We were encouraged, but not entirely surprised, to see a clear signal that gene therapy can safely accelerate healing,” he said. “What did surprise us was the magnitude and consistency of the effect across both 4-mg and 8-mg doses,” he noted.

The trial represents the first randomized, anatomically directed gene-therapy study to show a significant improvement in ulcer healing in people with CLTI, Armstrong emphasized. 

“If confirmed in larger phase 3 trials, it could complement surgical and endovascular approaches by targeting the microcirculation — bridging revascularization and regenerative medicine. In short, it hints at a future where we not only restore flow but also repair tissue,” he said.

As with any phase 2 trial, LEGenD-1 was limited by the small sample size and limited geographic and demographic scope. “While the safety profile was excellent, we need larger, more diverse studies to confirm durability, optimal dosing, and recurrence rates,” said Armstrong. “Future work should also incorporate mechanistic imaging and patient-reported outcomes to better understand how local angiogenesis translates into long-term limb preservation,” he added.

Results Bode Well for Wound Care

The research described is important because of the vast number of patients with PAD and CLTI, said Michael Maier, DPM, podiatrist and wound care specialist at the Cleveland Clinic, Cleveland, who was not involved in the study.

“These patients have many comorbid factors, and wound healing is critically important to restore their ability to walk and perform daily activities,” he told Medscape Medical News.

Maier added that he wasn’t surprised by the study findings and credited the investigators on a successful trial design. “It is very difficult to enroll patients in this type of study, and the results look promising for further research,” he noted.

“This type of advanced treatment sheds light on the complexity of patients with PAD/CLTI, including those with diabetes. These patients generally have poor outcomes, and optimizing blood flow and facilitating wound healing requires choreographed, multidisciplinary care,” said Maier. “Providers who care for diabetic patients should be aware of advanced therapies to identify and treat PAD in earlier stages.”

Patient compliance is important in any treatment plan, and the researchers did not go into detail on why approximately 25% of the patients withdrew, he noted. “Although likely not specific to diabetes, further discussion on those who withdrew early may help to identify barriers to treatment,” he said.

“Ongoing research into novel mechanisms of gene therapy delivery may prove helpful for these patients,” Maier added.

The study was supported by AnGes USA, Inc. Armstrong disclosed serving on the Scientific Advisory Board for the company, as well as receiving research support and reimbursement for travel and meeting expenses. 

Maier disclosed having no financial conflicts of interest.