Comparisons Between
OrCel® and Apligraf®
Comparative Histological ProfilesComparative Histological Profiles
Apligraf® OrCel®
Fully Differentiated and
Stratified Ke...
In Vitro expression of KGF and GMCSF
by cultured LSEand ORCEL
1
1000
1000000
KGF GM-CSF
CytokineOutputPerunitArea,pg/cm2/d...
Output, OrCel®
vs. Apligraf®
10
100
1000
10000
100000
bFGF GM-CSF HGF KGF-1 VEGF IL-1a MMP-9 PGE-2
CytokineProductivity,pg...
OrCel® in Donor Site Healing
(Independent Physician Evaluation:
Donor Site Treated with both OrCel® & Apligraf®)
OrCel®
Ap...
Days to
100% Healing
(Median)
 OrCel
Standard of
Care
DONOR SITES
Pivotal: 2/01
Based on Photography
0
2
4
6
8
10
12
14
1...
OrCelOrCel ™™ HealsHeals
Wounds FasterWounds Faster
47%
23%
0
10
20
30
40
50
60
Diabetic Foot Ulcers Pilot Trial
% of Pati...
Summary of OrCel® vs. Apligraf® Features
Feature OrCel® Apligraf®
Shape/Size Square 6.5 x 6.5 x 0.09 cm (42 cm2
) Round 75...
Summary: OrCel® vs. Apligraf® Data
• Pilot ORCEL (fresh) VLU trial data achieved closure in 12
weeks (59% vs. 36%) compara...
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Orcel vs apligraf v4

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Diabetic Foot Ulcer FDA Approved Treatment

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  • Note that Apligraf, shown in Trichrome stain, is top-heavy, containing a multi-layered “mature” stratum corneum with a high concentration of keratinocytes, but a rather sparse fibroblast population by comparison. Apligraf is about ¾ keratinocytes and has almost no dividing cells. OrCel, by comparison (shown in Hematoxylin/Eosin, or H&E stain), is over ¾ fibroblasts and has about 15% dividing cells. Apligraf has cells in a dense gel matrix, while OrCel cells are more sparse, are still growing in a very porous sponge matrix. In short, Apligraf cells are relatively quiescent, while OrCel cells are dynamic. The collateral effects of these differences can be seen in the two products’ relative cytokine expression levels in vitro (next slide).
  • In vitro Cytokine Expression by OrCel vs. LSE: Cultures of equivalent sized pieces of OrCel (freshly thawed and rinsed in saline solution) and Living Skin Equivalent, or LSE (Apligraf, freshly removed from its packaging at room temperature) in OrCel growth medium (Ortec International, Inc.) were incubated for 48 hr, and media were sampled daily; assay of KGF-I and GMCSF were by commercial ELISA kits (Quantikine, R&D Systems) following manufacturer’s recommendations. Results are expressed as picograms (pg) of cytokine secreted per square centimeter area of tissue per day.
  • This graph illustrates the relative output of specific cytokines, growth factors and Matrix Metalloproteinases by pieces of OrCel and Apligraf of identical area cultured in vitro under identical “transwell” (the Apligraf culture method) conditions. Note that the left side of the graph shows growth and migration stimulatory factors, while the right side shows pro-inflammatory factors. In terms of potency, GM-CSF, a keratinocyte mitogen and migration factor, is believed to be highly potent at >1000 pg/cm2/day, as above in the ORCEL bar, while the angiogenic response of the wound to VEGF is believed to be proportional to concentration above 1000 pg/cm2/day. The practical potency levels of the other stimulatory cytokines are not known. The higher MMP-9 and PGE-2 production by APLIGRAF imply that it is significantly more pro-inflammatory -- as evidenced clinically in the example on the next slide.
  • As you may know, there are two commercially available tissue engineered products which contain both epidermal and dermal cells…OrCel and Apligraf
    This photograph represents a direct head to head comparison of these two products on a single donor site wound.
    This is a burn patient who was treated at Doctors Hospital in Augusta, GA who had OrCel placed on her donor sites. The OrCel was placed on the right medial thigh…. And Apligraf was placed on the same donor site on the lateral aspect creating a direct side by side comparison of the two products. Note that ORCEL is “square” while Apligraf is “round.” This photo was taken 13 days after the original treatment.
    As you can see the OrCel treated area has re-epithelialized in a uniform fashion with an acceptable cosmetic outcome. Additionally, pigment is already returning to the OrCel treated area
    As you can see the Apligraf treated areas are not yet fully epithelialized and appear red slightly inflamed and not fully healed. This is significant not just from a cosmetic visual point of view but also because the earlier one can heal any open surface area on a burn patient the better it is for that patient.
  • These are the results from the Diabetic Ulcer Pilot Study. As you can see from the graph, 47% of OrCel treated patients achieved 100% wound closure by Week 12 compared to 23% of Standard Care treated patients.
  • Orcel vs apligraf v4

    1. 1. Comparisons Between OrCel® and Apligraf®
    2. 2. Comparative Histological ProfilesComparative Histological Profiles Apligraf® OrCel® Fully Differentiated and Stratified Keratinocytes Partially Differentiated, Non-Stratified “Wound Healing” (Migrating & Replicating) Keratinocytes Low Density Dermal Fibroblasts, Many Undergoing Apoptosis Medium Density, Vigorously Growing Dermal Fibroblasts (≥15% “Dividing” Cells)
    3. 3. In Vitro expression of KGF and GMCSF by cultured LSEand ORCEL 1 1000 1000000 KGF GM-CSF CytokineOutputPerunitArea,pg/cm2/day LSE ORCEL Living Skin Equivalent (LSE) is a generic name for Apligraf
    4. 4. Output, OrCel® vs. Apligraf® 10 100 1000 10000 100000 bFGF GM-CSF HGF KGF-1 VEGF IL-1a MMP-9 PGE-2 CytokineProductivity,pg/cm2 /day OrCel Apligraf Pro-mitotic Pro-Inflammatory
    5. 5. OrCel® in Donor Site Healing (Independent Physician Evaluation: Donor Site Treated with both OrCel® & Apligraf®) OrCel® Apligraf® OrCel®: Faster healing, less inflammation
    6. 6. Days to 100% Healing (Median)  OrCel Standard of Care DONOR SITES Pivotal: 2/01 Based on Photography 0 2 4 6 8 10 12 14 16 18 20 22 22 Days 15 Days PMA Claims •Accelerated healing •Less Scarring •Reduced time to recropping 
    7. 7. OrCelOrCel ™™ HealsHeals Wounds FasterWounds Faster 47% 23% 0 10 20 30 40 50 60 Diabetic Foot Ulcers Pilot Trial % of Patients Achieving 100% Wound Closure By 12 Weeks OrCel  OrCel  Standard of Care Standard Of Care
    8. 8. Summary of OrCel® vs. Apligraf® Features Feature OrCel® Apligraf® Shape/Size Square 6.5 x 6.5 x 0.09 cm (42 cm2 ) Round 75mm diam x 0.75mm (44cm2 ) Matrix Preformed porous cross-linked bovine collagen sponge, very pliant Contracted, dense, stiff bovine collagen gel Keratinocytes (K) Immature mono-/bilayer (submerged culture condition) Stratified multilayer (air interface culture condition) Fibroblasts (F) Healthy vigorously dividing Dormant or apoptotic Cell type ratio Nominal ~90% F ~10% K Nominal ~30% F ~70% K Cytokine profile F (& F/K co-culture) dominated; activated “wound healing” profile K (& F/K co-culture) dominated; normal skin steady state dormant profile Ease of use Semi-auto thaw/rinse (~20 min) & direct application Remove from dish, cut to size, fenestrate (~20 min) Shelf life 7 mo (clin. trial); expect 12 – 18 mo 10 days in sealed pkg. Current reimbursement $1,100./42 cm2 $1,200/44 cm2
    9. 9. Summary: OrCel® vs. Apligraf® Data • Pilot ORCEL (fresh) VLU trial data achieved closure in 12 weeks (59% vs. 36%) comparable to adjusted (Cox) Apligraf results at 6 months (56.8% vs. 39.8%); pivotal ORCEL (cryopreserved) clinical data are similar (50% vs. 31%). • Pilot ORCEL DFU trial data achieve results within 12 weeks (47% vs. 23%) comparable to Apligraf (56% vs. 39%) at 12 weeks (SOC differed) • ORCEL is easier to apply • ORCEL, since cryopreserved, has far superior shelf life (7- 12 months+ (projected) vs. 10 days) and can also be stored at the clinical site for “off-the-shelf” availability

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