Abstract Body (Do not enter title and authors here): Background
No FDA-approved therapeutics exist for patients with wounds and chronic limb-threatening ischemia (CLTI). AMG0001 is a plasmid DNA that encodes human hepatocyte growth factor(HGF). It has been shown to improve limb perfusion in randomized trials of people with CLTI. We hypothesize that HGF gene transfer via IM injection can promote wound healing and decrease ulcer recurrence in this patient population.

Methods
LEGEND 1 trial was a Phase II, double-blind, randomized, placebo-controlled trial enrolling 75 subjects with neuro-ischemic ulcers (eligible TP/TcP02s 30-59 mmHg) into one of three treatment arms (AMG0001 4 mg, 8 mg, or placebo) allocated 1:1:1. Calf IM injections targeted specific angiosomes based on wound location and imaging. Patients received 4 treatments at 1-month intervals. Healing was defined as complete epithelialization for 2 consecutive visits 14 days apart and independently adjudicated. Co-primary endpoints were time to healing and proportion of ulcers healed by 6m. Additional endpoints included ulcers healed by 12m, changes in hemodynamics, and ulcer recurrence.

Results
Population included 80% male, 71% with Type 2 DM, with a baseline mean toe, ankle, and TcPO2 pressures of 46 mmHg, 71 mmHg and 50 mmHg respectively in the index limb. Mean wound size was 3.4± 2.5 cm². There were no significant baseline differences between treatment arms. Median time to healing for pooled AMG0001 treatments was 84 days vs 280 days in the placebo arm (p =0.0071)(Fig 1). Proportion of ulcers healed by 12m for the pooled AMG0001 arms was 78% vs 46% for placebo (p= 0.0096). Proportion of those with complete healing by 6m for the pooled AMG0001 arms was 63% compared to placebo 39%, (p=0.053). Ulcer recurrence at 12m was 50% in the placebo arm vs 32% in AMG0001 arms(p=NS). Increases in ABI at 6m (0.13;p=0.03) and dorsal foot TcPO2 at 12m (18.5mmHg;p=0.02) were observed in the AMG0001 4.0 mg arm. Adverse events were evenly distributed.

Conclusions
Anatomically directed delivery of AMG0001 is well-tolerated and significantly improved time to complete healing in people with moderate CLTI and concomitant neuroischemic ulcers. HGF gene transfer may offer a promising alternative for the treatment of patients with CLTI.