Leon H Kircik M.D.

Transcription

Leon H Kircik M.D.

Leon H Kircik M.D.
Clinical Associate
Professor of Dermatology
Indiana University School of Medicine
Mount Sinai Medical Center
Physicians Skin Care, PLLC
Louisville, KY
© 2008 SkinMedica, Inc. All rights
reserved.
I have received funding either as an investigator, consultant,
or a speaker from the following pharmaceutical companies:
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Abbott
Acambis
Allergan
Amgen
Astellas
Asubio
Berlex
Biogen-Idec
Biolife
Breckenridge Pharma
Centocor
Colbar
Collagenex
Combinatrix
Connetics
Coria
Dermik
Dow
Dusa Pharmacueticals
Ferndale
Galderma
Genentech
Glaxo-Smith Kline
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HealthPoint
Intendis
Innovail
Johnson & Johnson
3M
Leo
Medicis
NanoBio
Novartis
Nucryst
Obagi
OrthoNeutrogena
Pfizer
PharmaDerm
QLT
Quatrix
Serono
SkinMedica
Stiefel
TolerRx
Triax Pharmaceuticals
UCB
Valeant
Warner & Chilcott
PAGE 2
reserved.
Functions of Human Skin that Decline with
Age
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Cell replacement
Injury response
Barrier function
Chemical
clearance
•  Sensory perception
•  Mechanical
protection
reserved.
•  Immune
responsiveness
•  Vascular
responsiveness
•  Thermoregulation
•  Sweat production
•  Sebum production
•  Vitamin D
production
PAGE 3
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Clinical Differences in Chronological Aging
& UV-Induced Premature Aging
UV-Induced Premature
Aging
Chronological Aging
•  Thin, dry, pale, delicate skin
•  Fine wrinkles
•  Fat atrophy
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Dry, rough, dull, yellowish skin
Deep lines and wrinkles
Elastosis, laxity
Dyspigmentation
(eg mottled hyperpigmentation,
lentigines, irregular
depigmentation)
Enlarged pores
Telangiectasia
Actinic keratoses
Skin cancers
PAGE 4
reserved.
UV Induces Loss of Collagen
UV exposure
↓
Reactive oxygen species (H202, OH•)
↓
↑ AP-1 induction
↑ collagenase
↑ gelatinase B
↓ procollagen I gene expression
↓  collagen
Fisher et al., 2000.
PAGE 5
reserved.
Collagen Loss and Repair
Leads to Wrinkles
•  Following UV exposure,
collagen is cleaved and
degraded by enzymes
•  Fragments can inhibit
collagen formation and
contribute to misrepair
•  Repeated collagen repair
results in
–  Disorganized collagen
matrix (imperfect repair of
collagen fragments →
subclinical microscars)
–  Permanent reduction in
collagen
–  Wrinkles
Sun
Damage
Fisher et al., 1997.
reserved.
PAGE 6
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The Spectrum of Skin Damage
Due to Sun Exposure
Roughness
Sunburn
Fine
Actinic
Wrinkling
Keratosis
Mottled
Deep
Carcinoma
Hyperpigmentation
Wrinkling
From: Focus on Photodamage: A Medical Problem. Parsipanny, NJ: Skin Phototrauma Foundation: 1990:2-28.
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reserved.
Histology of Sun-Damaged Skin
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Loss of collagen I, III, VII, and fibrillin → Wrinkling
↑ size and activity of melanocytes
→ Hyperpigmentation
Overall ↑ density of melanocytes
Irregular distribution of melanosomes within
epidermal keratinocytes
•  Localized absence of melanocytes →
Depigmentation → Irregular/mottled dyspigmentation
•  Cytologic atypia
•  Disorderly maturation of keratinocytes
→ Actinic
keratoses
reserved.
PAGE 8
Solar Elastosis
•  Elastin is major component in solar
elastosis but also contains elastin
associated microfibrils, fibrillin, fibronectin,
GAG, etc. but no normal elastic fibers with
typical morphology.
•  Therefore, these elastic structures are not
functional in providing elasticity and
resiliency to the skin.
reserved.
PAGE 9
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•  Medical
–  Non-Invasive
–  Economic
–  Minimal Side
Effects
–  ↓ Recovery Period
•  Surgical
–  Invasive
–  Cost
–  ↑ Recovery Period
–  ↑ Side Effects
–  ↑ Anesthesia
PAGE 10
reserved.
Noninvasive Management
of the Aging Face
•  Regenerate
–  Creams, Chemical peels, microdermabrasion,
nonablative “resurfacing”
•  Relax
–  Botox
•  Replace
–  Multiple injectable dermal fillers
PAGE 11
reserved.
What Are Growth Factors & Cytokines?
•  Naturally occurring proteins
capable of stimulating
–  Cellular Growth, Proliferation and
Differentiation
•  Produced by all cell types
including skin cells
–  Fibroblasts, Keratinocytes,
Lymphocytes, Mast cells
•  Generally act in close
proximity of their production
•  Cytokines are associated
with immune system cells
and play a key role in
modulation of inflammation
Two TGF-β3 molecules (red and blue)
binding to two receptors each (green and
yellow) to form an active complex.
Image courtesy of University of Texas Health Science
Center at San Antonio
reserved.
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Role of Growth Factors in
Inflammation and Skin Remodeling
•  Inflammation leads to
generation of ROS
and enzymes that
degrade ECM and
secrete GFs
•  GFs induce dermal
fibroblasts to initiate
ECM production and
skin repair
•  GFs further induce
dermal fibroblasts to
produce extended
dermal remodeling
ROS - Reactive Oxygen Species
ECM - Extracellular Matrix
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reserved.
Skin Aging
•  Over time, the body loses
the ability to complete the
healing process, resulting in:
–  Up to 20% reduction in
collagen1
–  Excessive type 3 collagen
–  Loss of stored antioxidants
–  Loss of skin elasticity
–  Wrinkle & fine line formation
References:
1. Schwartz E et al. Photochem
Photobiol 1993;53:841-844.
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reserved.
Role of Growth Factors in Reversal of Aging
•  GF active during skin
remodeling following are
crucial for the reversal of
aging
•  Through normal aging,
production and level of
growth factors decrease
1,2
Extrinsic
Aging
Intrinsic
Aging
•  Replenishing growth
factors in skin can induce
remodeling and reversal
of aging
References:
1. Mori Y et al., Arch. Dermatol Res
1998;290:158-162
2. Canalis E., J Clin Endocrinol Metabol
1994;78:1009-1010.
reserved.
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Can Topical GF Produce Response in
Dermis?
•  GF penetrate into
superficial epidermis and
initiate a communication
cascade1
•  Topical growth factors
bind to receptors on
epidermal keratinocytes2
•  Keratinocytes secrete
endogenous growth
factors that can stimulate
dermal fibroblasts1-3
References:
1: Ansel J, et al., J Invest Dermatol.
1990;94:101S-107S. 2: Werner S, et al. J Invest
Dermatol. 2007;127:998-1008. 3: Babu M, Wells A,
Wounds, 2001;13:183-189.
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reserved.
Physiologically Balanced Growth Factors
•  GF are part of a complex
cellular communication
network and work in
harmony with each other
•  Combinations similar to
those in physiological
environment must be
maintained to provide
optimal benefits
•  Like breast milk, ideal GF
combination cannot be
synthetically made
Schematic reprinted from:
Werner S, et al. J Invest Dermatol;127:998-1008; 2007
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reserved.
Effects of Aging on Growth Factors
•  Through normal aging,
production and level of
growth factors decrease1,2
•  Growth factor levels peak
in youth when our bodies
fully develop
1. Mori Y et al., Arch. Dermatol Res 1998;290(3):158-162
2. Canalis E., J Clin Endocrinol Metabol 1994;78(5):1009-1010.
reserved.
Copyright ©2007 SkinMedica, Inc. All rights reserved.
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How Topical Growth Factors Penetrate
Large molecules can penetrate into the skin
•  Through hair follicles and
sweat glands1,2,3
•  Through impaired skin
barrier4,7
•  As particles in the size
range of 10 -100nm5
•  With penetration enhancers
alter the lipid barrier6
1. Lademann J et al. Skin Pharmacol Physiol. 2006;19(4):232-236. 2. Yu WH et al., J Invest Dermatol. 1999 Mar;112(3):370-375. 3. Ciotti SN,
Weiner N, J Liposome Res. 2002 Feb-May;12(1-2):143-148. 4. Jakasa I, et al., Exp Dermatol. 2006;15:801-807. 5. Baroli B, et al., J. Invest Derm
2007; 127: 1701–1712. 6. Cui CY, et al. Biol Pharm Bull 2005;28:2279-2288. 7. Homey B, et al., Chem Immunol Allergy. 2007;93:181-194
reserved.
PAGE 19
NouriCel-MD®
A Unique Growth Factor Blend
NouriCel-MD is the solution in which
dermal fibroblasts grow in culture. It is
rich in human growth factors, soluble
collagen, antioxidants, and matrix proteins
–  FDA Approved Human
Fibroblast Cell Banks
–  Patented Advanced
Manufacturing Process
–  Active Source of Growth Factors
–  Stable Growth Factors
–  Proven Clinical Results
Collection of Sterile NouriCel-MD
PAGE 20
reserved.
Patented Manufacturing Process
Growing Living Human Tissues
Secreted Growth Factors Concentrated and Stabilized to Make
NouriCel-MD
reserved.
PAGE 21
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TNS Recovery Complex®
with NouriCel-MD®
•  Final Product:
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93.6% NouriCel-MD
•  NouriCel-MD Contains:
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110 growth factors and cytokines
Antioxidants
Matrix proteins
•  Aqueous Gel Formulation
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reserved.
Surfactant Free, Alcohol Free
Oil Free, Non-Comedogenic
PAGE 22
Key Growth Factors
•  Vascular Endothelial Growth Factor VEGF
–  Chemotactic and mitogenic to endothelial cells and promotes
angiogenesis
–  Believed to increase blood vessel permeability to improve tissue
nutrition
•  Platelet Derived Growth Factor PDGF AA, PDGF BB
–  Chemotactic and mitogenic to fibroblasts
–  Believed to regulate cell growth and division in wound healing
•  Transforming Growth Factor TGFβ1, TGFβ2, TGFβ3
–  Chemotactic and mitogenic to fibroblasts
–  Regulates matrix protein including collagen and proteoglycans
•  Tissue Inhibitor of Metalloproteinases TIMP1, TIMP2
–  Regulates activity of enzymes preventing breakdown of collagen and
hyaluronic acid
reserved.
PAGE 23
Supplemental Growth Factors
•  Fibroblast Growth Factors bFGF (FGF-2), FGF-4, FGF-6, KGF
(FGF-7), FGF-9
–  Believed to promote skin cell growth and tissue repair
•  Hepatocyte Growth Factor HGF
–  Believed to promote three dimensional tissue growth
•  Insulin Like Growth Factor IGF1, IGFBP1, IGFBP2, IGFBP3, IGFBP6
–  Believed to promote cell growth and multiplication
•  Placenta Growth Factor PLGF
–  Believed to promote endothelial cell growth
•  Bone Morphogenetic Protein BMP7
–  Believed to promote development of nerve cells in developing tissue
•  Interleukins (15 Different Interleukins including IL10 and IL13)
–  Believed to play a critical role in inflammation and wound healing
•  Colony Stimulating Factor GCSF, GM-CSF, M-CSF
–  Believed to induce secretion of other cytokines
reserved.
PAGE 24
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TNS Recovery Complex®:
Clinical Studies
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reserved.
Study Design
•  1:1 Randomized, vehicle-controlled, double-blind
study
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Protocol: Cetaphil Cleanser, Cetaphil moisturizer with sunscreen
•  60 subjects with facial photodamage enrolled and 58
completed
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Mild/Moderate photodamage: 48 subjects
Severe photodamage: 12 subjects
Females: 90%, Caucasians: 98%
Age range 41 to 65 (Mean age 55)
No adverse event related drop-outs
•  Evaluations at baseline, 1, 3 and 6 months by three
techniques:
1.  Optical profilometry
2.  Visia photographs and independent panel review
3.  Investigator’s assessment of photodamage
PAGE 26
reserved.
Skin Surface Impression:
Periorbital Area
Baseline
6 Months
Female
Age 63
reserved.
Female
Age 52
Female
Age 62
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Significant Reduction of
Skin Surface Roughness
PAGE 28
reserved.
Independent Panel Review
VISIA Images
Reviewers: Dr. James Leyden, Dr. Lisa Donofrio
and Dr. Timothy Flynn
CopyrightCopyright
©2008 SkinMedica,
©2008 All rights
Inc. All
reserved.
rights reserved.
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reserved.
6 Months
Baseline
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Investigators assessment:
Reduction in Photodamage
reserved.
PAGE 31
Double-blind Clinical Efficacy Trial:
Summary
In clinical studies, TNS Recovery Complex shows:
–  Statistically significant improvements over vehicle
control in:
•  Fine lines and wrinkles
•  Facial photodamage scoring
•  Peri-orbital wrinkling
–  Statistically significant improvements over baseline in:
•  Mottled pigmentation and tactile roughness
reserved.
PAGE 32
PBGF in Combination Therapy
•  Growth factors are critical in building
extracellular matrix
•  Other critical agents affecting the reversal
of aging are:
–  Free radical fighting agents
–  Matrix Metalloproteinases (MMP) Inhibitors
–  Anti-inflammatory agents
•  The best anti-aging product is a
combination of physiologically balanced
growth factors with other critical agents
reserved.
PAGE 33
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Agents Blocking Pathways of Skin Damage
AO
AO
AO
RE
GF
AI
AO
Antioxidants
(including Retinoids)
AI
Anti-inflammatory
RE
Retinoids
GF
Growth Factors
improving ECM quality
GF
PAGE 34
reserved.
TNS Essential Serum™
Chamber 1:
APS Corrective Complex™
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Peptides: Extracellular matrix
building
–  Dipalmitoyl Hydroxyproline
–  Palmitoyl Tripeptide-5
–  Hydrolyzed Silk
Antioxidants: Free-radical
scavengers
–  Ergothioneine (EGT)
–  Ubiquinone (Coenzyme Q10)
–  Tocopheryl Acetate
–  Tetrahexyldecyl Ascorbate
–  Rubus Fruticosus (Blackberry)
Leaf Extract
–  Camellia Sinensis (Green Tea)
Leaf Extract
Specialty Ingredients
–  Alpha-Arbutin-Skin lightener
–  Hyaluronic Filling Spheres:
Immediate filling of fine lines
–  Aminobutyric Acid (GABA)-Skin
tightening
reserved.
Chamber 2:
TNS Recovery Complex®
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93.6% NouriCel-MD®
–  110 Growth Factors and
Cytokines
–  Antioxidants
–  Matrix proteins
Aqueous Gel Formulation
–  Surfactant free, alcohol free
–  Oil free, non-comedogenic
High Protein Concentration: 50
mg/mL
–  Ensures stability of growth
factors
–  May improve chance of delivery
–  Includes penetration enhancers
Stabilized Cytokines and Growth
Factors
–  Surfactant-free formula protects
growth factors
–  Proven stability after 24 months
storage at room temperature
PAGE 35
PBGF Combination Therapy Clinical Study
•  PBGF mixture with multiple antioxidants,
peptides and specialty ingredients serum
•  Trookman NS, Rizer RL, Ho E, Ford RO, Gotz V.
Clinical Efficacy and Tolerance of a Novel Treatment
Serum for Photodamaged Facial Skin.
Poster presentation Annual AAD Meeting 2009
reserved.
PAGE 36
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PBGF Combination Therapy : Study Design
•  37 subjects enrolled
–  Twice daily product application in conjunction with a basic
skincare regimen including sun protection.
•  Evaluations at Baseline, 1, 2 and 3 Months:
–  Investigator Assessments
–  Elasticity by Cutometer
–  Digital Photography
Trookman et al. Poster presentation at Winter 2009 AAD annual meeting
reserved.
PAGE 37
Investigator Assessments: Skin Texture
reserved.
PAGE 38
Investigator Assessments: Peri-Orbital Wrinkles
reserved.
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Patient 12 Right Forehead
Age: 54
After 1 month of PBGF/
antioxidants/peptides
Before Treatment
PAGE 40
reserved.
Patient 28 Right Peri-Orbital Region
Age: 47
Before Treatment
PAGE 41
reserved.
Patient 52 Right Peri-Ocular Area
Age: 51
Before Treatment
After 3 months of PBGF/
reserved.
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Patient 4 Frontal View
Age: 40
Before Treatment
PAGE 43
reserved.
Patient 24 Left Peri-Ocular View
Age: 49
Before Treatment
After 2 months of PBGF/
reserved.
PAGE 44
Clinical Trial Evaluating Protection from UV
Radiation
•  Assessment of protection against UVinduced erythema after 10 days of twice
daily treatment (N=11)
•  TNS Essential Serum effect compared to
untreated site in same subject
•  Test skin sites were exposed to a 1 cm
diameter spot of UVA/UVB light.
–  UV radiation was supplied by an artificial source with UV
range comparable to that of natural sunlight.
Data on file SkinMedica
reserved.
PAGE 45
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Reduction in UVA/UVB Induced Erythema
1 MED
1.5 MED
1 MED
2 MED
1.5 MED
Un-treated
Data on file SkinMedica
MED = Minimal Erythemal Dose
2 MED
Treated
reserved.
PAGE 46
Reduction in UV Induced Erythema
Up to 50% Reduction in UV Induced Erythema in skin treated with
TNS Essential Serum over untreated skin
PAGE 47
reserved.
PBGF Combination Therapy
Summary of Clinical Results
•  Statistically significant improvements
observed in:
–  Textural Roughness -89%
–  Fine Wrinkles -30%
–  Coarse Wrinkles -44%
•  Statistically significant improvement in skin
elasticity
•  Statistically significant protection (50%)
from UVA/UVB exposure
reserved.
PAGE 48
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Conclusion
•  Human growth factors have a key role in
the reversal of aging process
•  A combination of growth factors affecting
multiple pathways of skin repair have been
shown to enhance reversal of skin aging
•  Combination therapy with PBGF,
antioxidants, peptides and other
ingredients has the potential to impact skin
aging and reverse the aging process
PAGE 49
reserved.
Discussion
reserved.
PAGE 50
17

Leon H Kircik M.D.

Transcription

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