Predictors of Wound Healing Used to Inform Design of a "precision" Phase 2 trial of Synthetic Matrix Protein/growth Factor Construct in Venous Leg Ulcers

It is well recognised that functional ECM is critical for normal wound healing. However, the ECM is often impaired in chronic wounds through proteolytic and oxidative damage associated with prolonged inflammation. With the aim of restoring the functional properties of the defective ECM in chronic wounds we developed a synthetic matrix protein (SMP) comprising a portion of vitronectin covalently linked to IGF-1. Binding studies demonstrate that the SMP is rapidly adsorbed onto decellularised dermal tissue through high affinity interactions with Collagen I, decorating the dermis with cell attachment sites and a localised source of IGF-1. In vitro analyses have shown that the SMP enables keratinocyte and fibroblast attachment and stimulates cellular migration and proliferation above levels observed for either vitronectin or IGF-1 alone. A single arm trial of topical SMP on hard-to-heal venous and mixed leg ulcers in conjunction with standard care has previously been reported. Primary endpoints for this 53 patient multicenter study were reduction in wound area and the number of patients healed within the 12 weeks treatment. No treatment-related SAE’s were observed. Healing time data were compared retrospectively to propensity score-matched data from UK patient databases using comparable covariants including aetiology, age, baseline ulcer area and ulcer duration. Kaplan – Meier survival curves showed a mean healing time of 83.5 days for the comparator untreated group and 73.1 days for SMP treatment (Log rank test, χ2 5⋅779, P = 0⋅016). Maximum benefit of the SMP treatment was observed in patients presenting with ulcers of moderate severity (≤5 cm2 and >6 months or > 5cm2 and <6 months). Guided by these predictive factors for healing we rationally designed and initiated a 168 patient, randomized, double-blind, placebo-controlled trial comparing two doses of SMP to placebo as an adjunct to standard care in patients with venous leg ulcers (NCT02973893).