Evaluation of Safety and Efficacy of realSKIN® (Skin Xenotransplant) for Complete Closure of Severe Burn Wounds

This is a Phase 1/2, Open-label, Multi-center, Clinical Trial to evaluate the safety, tolerability, and efficacy of realSKIN® to provide complete wound closure of severe and extensive deep-partial and full-thickness burn wounds.

Approximately 25 total subjects will be enrolled. Subjects who meet eligibility criteria and provide written informed consent will receive realSKIN® placement at a single burn wound site. The designated realSKIN® product size will be placed on the burn wound following wound site preparation, including necessary debridement and tangential excision as determined by burn surgeon and secured in place via suturing or stapling. The remaining burn wound will be covered with human cadaver allograft and treated according to local standard of care with care to avoid any overlap or significant contact of the two temporary wound dressings. The Investigator will assess the wounds and identify the matched pair of burn sites then the treatments will be randomly assigned to the sites.

realSKIN® will remain in place until intentional removal per Investigator's direction consistent with subject's overall clinical course, or if it is deemed to no longer provide effective wound closure and barrier function to the wound bed. The Investigator will follow local standard of care relevant to wound care and dressing changes while the realSKIN® is in place. Standard of care burn management will be provided by the Investigator.

Routine vital sign assessments, photography, laboratory tests (hematology, chemistry, and urinalysis), physical exams, and adverse event monitoring will occur while realSKIN® is in place and for up to 1 year following initial placement. Subjects will be monitored via a passive and active screening program using blood samples collected at time points throughout the study period, as adapted from FDA Guidance for Industry.

The risk of transmission of infectious disease is expected to be extremely low and while limited human trial data are available there have been no reports of transmission of porcine microorganisms to humans, and to date, there have been no adverse events (AEs) related to the use of realSKIN® observed or reported, and independent analysis of PERV data and medical records by the Safety Review Committee has indicated no evidence of zoonotic transmission in this trial.

Product Name: realSKIN®

Chemical Name: alpha-1,3-galactosyltransferase knock-out (GalT-KO) porcine (Sus scrofa) epidermal and dermal layers.

Chemical Structure: realSKIN® a biologically active, split-thickness, xenotransplantation skin product. realSKIN® is derived from specialized, genetically engineered (alpha 1,3 galactosyltransferase knockout \[GalT-KO\]), Designated Pathogen Free (DPF), porcine donors, containing vital, metabolically active (i.e., non-terminally sterilized) porcine cells within the dermal and epidermal tissue layers.

Proposed Indication: realSKIN is indicated for the treatment of mixed-depth, full-thickness burn wounds requiring hospitalization, surgical excision, and skin grafting.

Drug Type: realSKIN® is classified as a Live Biotherapeutic Product (LBP). (Guidance to Industry, Early Clinical Trials with Live Biotherapeutic Products, Section 1.b.)

Active Ingredient: Live (i.e. non-terminally sterilized) porcine cells, including endothelial cells of intact vasculature and those comprising the dermal and epidermal tissue layers

Product Structure: realSKIN® has an approximate thickness of 0.022 inches (0.55mm) and is currently provided in one investigational size: approximately 5x15 cm2 (22.5g/75 cm2).

Formulation: Each lot or releasable batch of realSKIN® is derived from a single source animal and each batch is independently processed and tested for various adventitious agents, histology, morphology, sterility, and purity.

Route of Administration: Surgical engraftment, via sutures or staples

Dosing Regimen: A single topical application of realSKIN has an approximate size of 150 cm2, with dimensions of 5 cm x 15 cm, meshed in a 2:1 ratio, and has an approximate thickness of 0.022 inches (0.55 mm).

realSKIN is intended for a one-time, topical application to a surgically prepared wound bed via sutures or staples and may be trimmed to fit the shape and size of the actual wound area. realSKIN can be used in the treatment of an overall injury size of up to 30% TBSA burn injury.

Drug's Mechanism of Action: realSKIN is intended for topical use directly on debrided, severe and extensive, mixed-depth and full-thickness burn wounds to provide complete and durable wound closure.

As a living skin transplant, realSKIN forms microvascular connections with host vessels in the burn wound bed which leads to wound closure. realSKIN replaces elements of whole, living skin that are analogous and functionally equivalent to those found in healthy human skin. realSKIN does not remain permanently engrafted but is replaced by the patient's own cells over time.

This mechanism of action distinguishes realSKIN from traditional xenograft products which are terminally sterilized, rendering the cells inactive, limiting their therapeutic capability to effect complete and durable wound closure.

Drug Packaging: Each realSKIN® product is individually packaged in a clear plastic, externally threaded, 10-ml polypropylene vial with threaded seal-cap, stored on a rolled, sterile nylon mesh backing on the dermal-side of the realSKIN® product that serves to support and protect the graft during processing and transport. Within this container, each realSKIN® product is individually immersed in 7-ml of sterile cryoprotective medium with 5% dimethyl sulfoxide (DMSO) (CryoStor CS5, BioLifeSolutions). Source animal serum is NOT included or used in this process. The contents are cryopreserved via controlled rate, phase freezer and stored at -80o C until use. All packaging materials are removed prior to the surgical procedure and dressing placement.

Eligibility Criteria:
Inclusion Criteria:

1. The subject provides written informed consent to participate in this study
2. Males or females age greater than 18 years old
3. Females must have a negative serum pregnancy test at Screening and at Baseline and must not be nursing
4. Male and female subjects must agree to use a protocol-approved method of contraception for a minimum of 3 months following Xeno-Skin® placement, which includes a barrier method plus one or more of the following:

   1. Hormonal contraceptives (e.g., birth control pills, skin patches, vaginal rings, and the Depo- Provera shot)
   2. Intrauterine device (IUD)
   3. Male or female condoms with spermicide
   4. Diaphragm with spermicide
   5. Permanent tubal occlusive birth control system
5. Total Body Surface Area (TBSA) \<30%, to include deep-partial thickness or full-thickness burn wounds
6. Burn injuries would otherwise require debridement and tangential excision
7. Burn injury requiring temporary grafting with human cadaver allograft skin, based on clinical judgment prior to definitive wound closure via autologous grafting
8. Sufficient area of burn wound for Xeno-Skin® placement and not located on face or hands or having an engraftment site centered on high-impact areas such as joints, weight-bearing areas (e.g. soles of feet), or the inguinal region, per Investigator's judgment

Exclusion Criteria:

1. Pregnant or lactating women
2. Documented history of infection with human immunodeficiency virus (HIV) or other condition(s) that in the opinion of the Investigator may compromise patient safety or study objectives
3. Immunosuppressive medication regimens e.g. antineoplastics, high dose steroids (\> 10 mg prednisone/day), TNF alpha inhibitors, calcineurin inhibitors (cyclosporine, tacrolimus), anti-proliferative agents, and other immunomodulators
4. Known allergy to penicillins (such as ampicillin), ceftazidime or aztreonam, glycopeptide antibiotics (such as vancomycin) or amphotericin B
5. Active malignancy, including those requiring surgery, chemotherapy, and/or radiation in the past 5 years. Non-metastatic basal or squamous cell carcinoma of the skin and cervical carcinoma in situ are allowed
6. Use of any experimental or investigational drugs within 30 days prior to placement of Xeno-Skin®
7. Previously received a porcine or other xenogeneic tissue product, including but not limited to: glutaraldehyde fixed porcine or bovine bioprosthetic heart valve replacements and glutaraldehyde fixed porcine dermal matrix (e.g., EZ Derm)
8. BMI \> 40 kg/m2
9. HbA1c ≥ 7.0%
10. Treatment with systemic corticosteroids within 30 days before screening (not including inhaled steroids)
11. Electrical, chemical, or radiation burns
12. History of chronic end stage renal disease defined as an MDRD CrCl \< 15 mL/min, or receiving chronic dialysis
13. History of chronic liver disease or cirrhosis (Child-Pugh Score C). Evidence of acute or chronic hepatitis B infection based on documented HBV serology testing
14. Known documented history of Hepatitis B, Hepatitis C, Treponema pallidum, Cytomegalovirus, herpes or varicella zoster Note: Successfully treated hepatitis C patients without evidence of end stage liver disease is allowed. If HCV antibody reactive, then HCV RNA must be undetectable.
15. Recent (within 3 months prior to study enrollment) MI, unstable angina leading to hospitalization, uncontrolled, CABG, PCI, carotid surgery or stenting, cerebrovascular accident, transient ischemic attack (TIA), endovascular procedure or surgical intervention for peripheral vascular disease or plans to undergo a major surgical or interventional procedure (eg, PCI, CABG, carotid or peripheral revascularization)
16. Presence of venous or arterial vascular disorder directly affecting the area of burn wound
17. Pre-existing haemolytic anemia
18. Chronic malnourishment as determined by Investigator
19. Significant pulmonary compromise
20. Systemic anticoagulation at the time of treatment or INR \> 2
21. Documented evidence of wound infection at Screening or Baseline
22. Evidence of sepsis and/or end organ damage
23. Acute lung injury
24. Life expectancy of less than 180 days
25. Subject who is unable to self-consent