Chronic Wound Preclincial and Clinical Studies to Date
Researchers from the University of Sydney have undertaken a number of preclinical studies to demonstrate that wt-APC and 3K3A-APC were effective in healing chronic wounds. In vitro studies included an assessment of human skin keratinocytes isolated from neonatal foreskin that were treated for 24 hours with increasing concentrations of wt-APC, 3K3A-APC or phosphate buffered saline (PBS) as a control group. These experiments were completed in conjunction with in vivo experiments and 3K3A-APC was shown to be more potent than wt-APC. Additionally, experiments conducted on cultured human cells showed that APC up-regulates the angiogenic promoters matrix metalloproteinase-2 in skin fibroblasts and umbilical vein endothelial cells, vascular endothelial growth factor in keratinocytes and fibroblasts, and monocyte chemoattractant protein-1 in fibroblasts. These results showed that APC promotes cutaneous wound healing via a complex mechanism involving stimulation of angiogenesis and inhibition of inflammation.
Researchers also have studied 3K3A-APC in vivo. An animal study to assess increasing concentrations of wt-APC, 3K3A-APC or Phosphate Buffered Solution (PBS) as control administered topically once a day for three consecutive days to full-thickness skin wounds of 7-8 week old mice showed that 3K3A-APC enhanced wound healing compared to PBS and wt-APC.
A series of clinical experiments were conducted in human cohorts with wt-APC, as well. Topical APC was studied on chronic lower leg ulcers in diabetic patients. Patients were assigned to receive either APC or physiological saline in a randomised, placebo-controlled double-blind pilot clinical trial. Treatment was administered topically, twice weekly for 6 weeks with final follow up at 20 weeks. Wound area was significantly reduced following APC treatment. Full-thickness wound edge skin biopsies showed reduced inflammatory cell infiltration and increased vascular proliferation following APC treatment. In this figure, a diabetic patient with an open wound on his foot that did not respond to 4 years of standard treatment had complete wound closure in 20 weeks with 6 weeks of dosing with wt-APC.
An assessment of whether combined treatment of topical negative pressure (TNP) and APC was tolerated and efficacious for treatment of difficult-to-treat wounds was also studied. Four patients who were non responsive to conventional therapy were studied and showed a marked reduction in wound size and depth within 1 week of starting treatment and progressively improved over time. Wounds either completely closed or provided sufficient granulation tissue to allow split-thickness skin grafting. APC was well tolerated in this study.
APC was also evaluated in the treatment for ulcers related to cutaneous Pyoderma Gangrenosum (PG). Patients were recruited with clinical history and examination and histopathological evidence of acute PG. APC was injected subcutaneously into the dermal edge of necrotic PG ulcers weekly over 6 weeks. APC led to a reduction in wound size, depth of ulcers, pain scores and a pronounced reduction in size between week 8 and week 12.
ZZ Biotech is currently performing necessary preclinical studies to support opening an IND in the Division of Dermatology in 2017 to start a Phase 2 study in diabetic foot ulcer patients with 3K3A-APC. Recalcitrant diabetic ulcers were selected as an initial target since they are generally more resistant to healing than other types of wounds and would potentially provide a strong efficacy signal.