Anatomically Directed Lower Extremity Gene Therapy for Ulcer Healing: A Double-Blind, Randomized, Placebo-Controlled Study (LEGenD-1)

BACKGROUND: People with chronic limb-threatening ischemia lack Food and Drug Administration-approved therapies for wound healing, creating an unmet need for novel approaches. Prior studies of biologics in chronic limb-threatening ischemia have largely targeted end-stage patients with amputation-free survival as the primary outcome. This trial evaluated the efficacy of intramuscular administration of AMG0001, a plasmid encoding human HGF (hepatocyte growth factor), to promote ulcer healing in patients with chronic limb-threatening ischemia and neuroischemic ulcers. METHODS: LEGenD-1 was a double-blind, randomized, placebo-controlled phase II trial conducted at 22 US sites. Seventy-five participants with neuroischemic ulcers and toe pressure or transcutaneous oxygen pressure between 30 and 59 mm Hg were randomized to receive AMG0001 at 4 mg, 8 mg, or placebo. Injections were administered intramuscularly along an angiographically guided target artery path on days 0, 28, 56, and 84. The 2 coprimary end points were time to complete healing and the proportion of subjects with ulcers healed by 6 months in a pooled AMG0001 analysis. Secondary end points included healing by 12 months, ulcer recurrence, and hemodynamic changes. RESULTS: Baseline characteristics were comparable across groups (mean age 62.6 years; 80.0% male; 70.7% with diabetes). Mean toe pressure was 46.1 mm Hg, and transcutaneous oxygen pressure was 49.8 mm Hg. Median time to healing was significantly shorter with AMG0001 versus placebo (84 versus 280 days; P =0.007); 4 mg: 98 days ( P =0.017); 8 mg: 84 days ( P =0.022). By 6 months, 63.3% of AMG0001-treated participants healed versus 38.5% of placebo ( P =0.053). By 12 months, healing rates were 77.6% versus 46.2% ( P =0.010). Adverse events were similar across groups. CONCLUSIONS: Anatomically targeted intramuscular delivery of AMG0001 significantly accelerated healing in patients with moderate chronic limb-threatening ischemia and neuroischemic ulcers and may represent a promising nonsurgical therapeutic strategy. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04267640.