Gene therapy for diabetic foot ulcers: Interim analysis of a randomised, placebo‐controlled phase 3 study of VM202 (ENGENSIS), a plasmid DNA expressing two isoforms of human hepatocyte growth factor

Abstract

To evaluate the status of a 7‐month phase 3 study conducted to test the effect of intramuscular injections of VM202 (ENGENSIS), a plasmid DNA encoding human hepatocyte growth factor, into the calf muscles of chronic nonhealing diabetic foot ulcers with concomitant peripheral artery disease. The phase 3 study, originally aimed to recruit 300 subjects, was discontinued because of slow patient recruitment. An unprespecified interim analysis was performed for the 44 subjects enrolled to assess the status and determine the future direction. Statistical analyses were carried out for the Intent‐to‐Treat (ITT) population and separately for subjects with neuroischemic ulcers, using a t‐test and Fisher's exact test. A logistic regression analysis was also conducted. VM202 was safe and potentially should have benefits. In the ITT population (N = 44), there was a positive trend toward closure in the VM202 group from 3 to 6 months but with no statistical significance. Levels of ulcer volume or area were found to be highly skewed between the placebo and VM202 groups. Forty subjects, excluding four outliers in both arms, showed significant wound‐closing effects at month 6 (P = .0457). In 23 patients with neuroischemic ulcers, the percentage of subjects reaching complete ulcer closure was significantly higher in the VM202 group at months 3, 4, and 5 (P = .0391, .0391, and .0361). When two outliers were excluded, a significant difference was evident in months 3, 4, 5, and 6 (P = .03 for all points). A potentially clinically meaningful 0.15 increase in Ankle‐Brachial Index was observed in the VM202 group at day 210 in the ITT population (P = .0776). Intramuscular injections of VM202 plasmid DNA to calf muscle may have promise in the treatment of chronic neuroischemic diabetic foot ulcers (DFUs). Given the safety profile and potential healing effects, continuing a larger DFU study is warranted with modifications of the current protocol and expansion of enrolling sites.

Scaffold-based synergistic enhancement of stem cell effects for therapeutic angiogenesis in critical limb ischemia: an experimental animal study

“…Cell-based therapies have been reported as a viable alternative in no-option CLI patients, and there are many ongoing phase III trials worldwide trying to develop a medical solution for the treatment of ischemia in different tissues [ 19 ]. Despite these efforts, it is not yet being widely used in our daily practice.…”

Translational Challenges in Drug Therapy and Delivery Systems for Treating Chronic Lower Extremity Wounds

“…However, challenges with protein drug stability and controlled release have resulted in safety concerns, particularly regarding its use in patients with neoplastic co-morbidities [ 90 ]. Overall, the application of exogenous growth factors provides a promising treatment for chronic wounds, and there are ongoing clinical trials, such as for VM202, a human hepatocyte growth factor [ 91 ]. However, developing systems for sustained localized drug delivery to mitigate off target effects and increase efficacy may be challenging.…”