Skin substitutes: Which ones really help heal ulcers and if so, when should we use them? Bill Marston, MD Professor and Chief, Division of Vascular Surgery Director, Wound Healing/Limb Salvage Center University of North Carolina Medical School

Disclosures Spiracur Organogenesis Healthpoint/Smith and Nephew Scientific consultant Organogenesis Healthpoint/Smith and Nephew Clinical trial investigator

Ancillary Therapies for Chronic leg ulcers Growth Factor Becaplermin Living cellular therapies Apligraf Dermagraft Non-living matrix dressings Oasis Other skin subs Negative pressure therapy Hyperbaric oxygen Revascularization Total contact casting Noninvasive Strategies Altered Mechanical Environment Charcot Foot

“Active” healing modalities Stimulate more rapid wound healing by Accelerated angiogenesis Stimulation of growth factor release Providing wound matrix for cellular ingrowth Production of required proteins/GFs FDA approved for healing DFUs Platelet-derived growth factor (Becaplermin) Living human dermal substitutes Apligraf Dermagraft

Factors for Not Healing: Cohort Study Margolis DJ, et al. Diabetes Care. 2002;25(10):1835-1839.

4-Week 50% Reduction Coerper S, et al. J Diabetes Complications. 2009;23(1):49-53.

If a wound has not healed 30-50% in a month with a specific treatment plan it is very unlikely to heal completely with another 8-12 weeks of the same plan

When to consider ancillary Rx High risk of poor healing on initial evaluation Poor response to initial trial of standard treatment modalities Debridement Bacterial control Offloading Adequate blood/O2 supply established if possible

Preparation for adjuvant skin subs

Engineered Human Skin Equivalents for chronic wounds Living Cellular Apligraf Dermagraft Non-living animal Oasis Primatrix Human sourced non-living Grafix Theraskin

APLIGRAF

Human Dermal Fibroblasts CYTOKINE EXPRESSION IN APLIGRAF AND HUMAN SKIN Human Keratinocytes Human Dermal Fibroblasts Apligraf Human Skin FGF-1 FGF-2 FGF-7 ECGF IGF-1 IGF-2 PDGF-AB TGF- IL-1 IL-6 IL-8 IL-11 TGF-1 TGF-3 VEGF + – + – + + FGF = fibroblast growth factor; ECGF = endothelial cell growth factor; IGF = insulin-like growth factor; PDGF = platelet-derived growth factor; TGF = transforming growth factor; IL = interleukin; VEGF = vascular endothelial growth factor.

Apligraf: venous leg ulcer pivotal trial 240 patients Ulcers present > 1 month Average 3.3 applications Applied with compression Percent closed at 24 weeks compared to compression alone 57% 40% P=0.02

Apligraf in diabetic foot ulcers 208 patients randomized prospectively 24 wound care centers All received standard wound care, etc followed 12 weeks 56% 38% P=0.003 47% increased probability of healing

Apligraf: venous leg ulcer pivotal trial 47% 66 73% 19% N=120 N=120 P = NS P = 0.002 Ulcer duration > 1 year Ulcer duration < 1 year

Number needed to treat to heal additional wound 6 patients with AG Cost for each additional healed wound $15,000 - 25,000 PLAVIX: To prevent an ischemic event Need to treat 59 patients with plavix instead of ASA Cost for each prevented event $85,000

OASIS Porcine small intestine submucosa Processed to lyse submocosal cells and remove debris Sterilized w ethylene chloride process Contents Acellular collagen-based ECM Functions as support structure for rapidly growing/active mucosal layer

Bioactive FGF-2 found at significant concentrations in matrix Wounds 2001;13:195-201

Apply and Wet

Prospective randomized trial of Oasis for Leg Ulcers 120 patients randomized to SOC or SOC plus Oasis application weekly Standard of care Debridement as needed Cover with non-adherent foam dressing Application of multi-layer compression bandage Weekly dressing changes

Venous Ulcer Study Results 120 total patients 62 SIS + SOC 58 SOC Gender Male Female SIS 29 33 SOC 21 37 Age Mean Range SIS 66 (21-90) SOC 65 (36-93) 96 patients completed the study (follow-up available until healing or through 12 weeks) 50 in SIS group 46 in SOC group 120 patients were enrolled in the trial and 96 completed the trial either to an endpoint of healing or the 12 week time period. Patient dropouts were due to withdrawal of consent, protocol violations, hospitalization/complications. The SOC and SIS arms of the study were roughly equivalent in terms of numbers included, gender and age 20% dropout rate

Oasis VLU Study: Time to healing 20/58 =34% Standard P=.02

Comparative studies using “real world” data

Wound Expert-derived data 1801 venous leg ulcers 1451 treated with BLCC (Apligraf) 350 treated with SIS Baseline wound patient demographics and wound characteristics similar

Wound closure up to 36 weeks

Other skin substitutes Integra Graftjacket Primatrix Gammagraft Alloderm Talymed Theraskin Grafix Ezderm Epifix

Grafix 3-dimensional cellular matrix produced from placental membrane contains 510K approved by FDA for treatment of chronic wounds At SAWC last year presented interim results on randomized trial in DFUs

Grafix study design 131 patients enrolled with DFUs 1-15 cm sq and ABI > 0.7 and < 1.3 1:1 randomization to control dressings or Grafix Single blind design CPC clinical research CRO performed independent oversight and confirmation of wound size and closure data

Top-Line Data from the Interim Analysis of Protocol 302             Grafix Control P-value (n=50) (n=47) Primary Complete Wound Closure at 12 Weeks 62.0% 21.3% p < .01   Secondary Complete Closure for Pts Receiving All Treatments* 71.4% 27.0% p=0.0001 Time to Complete Closure 42 days 70 days p=0.017 Number of Treatments to Closure 6 12 p=0.0001 Safety Patients with at least One Adverse Event 38.0% 66.0% p=0.008 Awaiting final results along with peer-reviewed publication to evaluate methods. Do the results relate to real wound patients?

Other skin equivalents with well designed validated randomized studies

Methods to optimize results with skin equivalents in DFU Optimize offloading Eliminate biofilm/bacteria Consider biopsy for culture in wounds of long duration Proper debridement to eliminate all non-viable tissue

Questions?