Gene Therapy Accelerates Ulcer Healing in Limb-Threatening Ischemia, With David Armstrong, DPM, PhD

Anatomically targeted delivery of AMG0001 gene therapy substantially accelerated healing in patients with moderate chronic limb-threatening ischemia and neuroischemic ulcers, according to results from the LEGenD-1 trial.1

Patients with chronic limb-threatening ischemia have historically lacked US Food and Drug Administration (FDA)-approved therapies for wound healing. Previous studies of biologics in this disease have typically targeted end-stage patients with amputation-free survival as the primary outcome. However, LEGenD-1 established a unique endpoint of time to complete ulcer healing.1

“For the longest time, people with significant blood flow compromises to their extremities, and particularly those with wounds, haven’t had any specific therapy, either pharmacologic, device or anything that really held promise in tissue repair and wound healing,” David Armstrong, DPM, PhD, a podiatric surgeon with Keck Medicine of USC, told HCPLive in an exclusive interview. “To see this happen now, and with some of these promising initial results, is really life-affirming.”

LEGenD-1 was a phase 2, double-blind, randomized, placebo-controlled, parallel group study conducted across 22 locations. Patients were eligible for enrollment if they had a documented diagnosis of PAD and mild/moderate foot ischemia and a single measurable ulcer of ≥1 cm2 and ≤10 cm2 on a lower extremity without infection or gangrene and no bone and/or tendon involvement, among other criteria. Patients were excluded if they exhibited excess tissue necrosis, had severe limb ischemia, deep ulcerations with bone/tendon exposure, or hemodynamically significant aorto-iliac occlusive disease, among other criteria.1,2

The study had 2 coprimary endpoints. The first was complete ulcer healing at 6 months, defined as skin re-epithelialization without drainage or dressing requirements confirmed at 2 consecutive study visits. The second was time to complete ulcer healing, defined the same way, at month 12. Secondary endpoints included the percentage reduction of ulcer size from baseline, hemodynamic measurements of toe pressure and ankle systolic pressure, occurrence of new ulcers in the index leg, and major/minor amputations or revascularization of the index leg, among other criteria.2

A total of 75 patients with neuroischemic ulcers and toe pressure or transcutaneous oxygen pressure between 30 and 59 mmHg were enrolled in the study. Investigators randomly assigned them to receive either AMG0001 4 mg, 8 mg, or placebo. Injections were administered intravenously along a target artery path on days 0, 28, 56, and 84.1

The mean age among patients was 62.6 years, the mean toe pressure was 46.1 mmHg, and the transcutaneous oxygen pressure was 49.8 mmHg. Ultimately, investigators saw a substantial reduction in median time to healing among patients treated with AMG0001 versus placebo (84 vs 280 days; P = .007). AMG0001 4 mg demonstrated a 98-day time to healing (P = .017), while 8 mg saw an 84-day time to healing (P = .022). By 6 months, 63.3% of patients receiving AMG0001 healed, versus 38.5% of placebo recipients (P = .053). By month 12, healing rates were 77.6% versus 46.2% (P = .01).1

“There’s so much great stuff going on now with GLP-1 RAs and PCSK9s – it’s a super exciting time to be working in this area,” Armstrong said. “But I’m more enthusiastic than ever about eliminating preventable amputation in these patients over the next generation.”

Editor’s Note: Armstrong reports disclosures with AnGes, Podimetrics, Endo Pharmaceuticals, Janssen, and Nevro.

References

1. Armstrong DG, Conte MS, Mills JL, et al. Anatomically directed lower extremity gene therapy for ulcer healing: A double-blind, randomized, placebo-controlled study (legend-1). Circulation: Cardiovascular Interventions. Published online November 4, 2025. doi:10.1161/circinterventions.125.015648

2. AnGes USA, Inc. Study of AMG0001 to Improve Ulcer Healing and Perfusion in Subjects With Peripheral Ischemic Ulcers. ClinicalTrials.gov Identifier: NCT04267640. Updated December 22, 2021. Accessed January 12, 2026. https://www.clinicaltrials.gov/study/NCT04267640