Transcript Slide 1 - Transdermal Corp

A Novel Topical Transdermal
Delivery System
Mark S. Nestor, M.D., Ph.D.
Director
Center for Clinical and Cosmetic Research
Aventura Florida
Topical Drug and Cosmetic Delivery





The skin is a formidable barrier against environmental
assaults as well as topical drug delivery
A variety of active compounds have significant activity
in the skin, subcutaneous tissue or muscle but cannot
adequately permeate the intact skin
Diseases such as acne, psoriasis, rosacea, and melasma
as well as cutaneous aesthetic enhancement could
dramatically benefit from our ability to better transport
active compounds to target tissue
Solutions to a 100+ billion dollar market
Ionic Nano Particle Technology (InParT) is a novel and
unique passive delivery system that can be utilized to
assist the transport of a variety of active compounds to
target sites in the skin and beyond
InParT Drug Delivery System
Ionic Nano Particle Technology I
 Novel,
commercially viable trans
dermal non-invasive drug delivery
technology that enables delivery and
absorption of active compounds
through the stratum corneum and
throughout the skin and sub
cutaneous tissue without any
cutaneous toxicity
InParT Drug Delivery System
Ionic Nano Particle Technology II
 Nano
particles are made from combinations of
micelles (surfactants and protein solubilizers),
coated with lipid molecules
 Nano paticles size; less than 1-10 nano meters
smaller than the skin pores
 Nano Particles Physically entraps active without
any changes in the chemical composition
 Stabilizes the actives: shelf stable at room
temperature for extended period of time without
refrigeration)
 Uses all FDA approved ingredients
InParT Drug Delivery System
Ionic Nano Particle Technology III

INParT technology is highly adaptable to most high
molecular weight drugs, proteins, peptides and
insoluble hydrophobic molecules
 Capable of delivering more than one therapeutic agent
at a time
 Offers high market value by featuring maximum
functionality at minimum system complexity and cost
 The technology is easily scalable to any size without
any complex new equipments need (no capital
expenditure, commercially viable)
SEM-Photograph- 250x
SEM-Photograph- 1000x
InParT Drug Delivery System
Clinical Investigation
 Topical
Hyaluronic Acid
 Topical Lidocaine
 Acne

Benzoyl Peroxide (BP)
 Topical
Botulinum Neurotoxin Type A
(BoNTA)


Rhytids
Hyperhidrosis
 Future
Developments and Partnerships
Topical Hyaluronic Acid
(HA)
InParT Drug Delivery System
Topical Hyaluronic Acid (HA)
HA crosslinked or non crosslinked difficult to
adequately penetrate the stratum corneum
If adequate penetration can be achieved topical
cross linked HA can significantly improve fine
lines as well as skin texture



Painless application
Companion treatment to injectable crosslinked HA
Topical cosmecutical
Topical Hyaluronic Acid (HA)
Clinical Model
The stabilized cream is applied topically onto the
skin containing crosslinked (non crosslinked)
HA
The nano-spheres helps penetrate the skin layers
with the aid of absorption enhancers and
releases the HA into the deep layers of the skin
HA incorporated into the dermis (rapid aesthetic
benefit) and induces long term collagen
synthesis
A Double Blind Vehicle Controlled Trial
to Investigate the efficacy and
tolerance of Transdermal CL1
(Restylane) versus non-CL1 (Non
Crossed Linked HA) in the appearance
of photodamaged skin
Topical Hyaluronic Acid (HA)
Clinical Trial I
100 subjects 2 sites: Women 35 – 65 with
moderate to severe photodamage: 40 CL1
(crosslinked HA – Restylane), 40 NCL1 (Non
crossed linked HA), 20 Vehicle
2 US sites
Subjects and investigators blinded
2 week wash out, 12 week trail (evaluations 2,6
and 12 weeks), 4 week post treatment
(washout)
Apply
twice a day clean face
.
Topical Hyaluronic Acid (HA)
Clinical Trial II
Visia camera system
Objective evaluations
Goldman-Rao” photographic scale in 5
grades
 Evaluation of skin roughness, skin
hydration, skin radiance, smoothing effect,
overall efficacy and tolerance

Subjective Questionnaires :
Product Qualities
.
 Subjective improvement

Topical Hyaluronic Acid (HA)
Clinical Trial - Washout
Evaluation of sustained effect of topical
HA
Patient discontinued all Topicals at day 90
and were evaluated for sustained effects
at day 120
Visia photographs
Clinical evaluations
.
Trial Data
Blinded Investigator Assessments
Clinical Evaluation: Skin Roughness
Clinical Evaluation: Skin Roughness
3
2.8*
2.6*
2.5
2.4+
2.3+
2
2
1.8
1.7
1.7
1.6
1.5
1.3
1.5
1.4
1.3
1.1
1
day 0
day 15
day 45
CL1
CL1: Crosslinked HA (Restylane)
NCL1
NCL1: Non Crosslinked HA
day 90
Control
day 120
* CL1 vs Control at .001
+NCL1 vs Control at .001
Control: Nano Technology Vehicle
Clinical Evaluation: Skin Roughness
Clinical Evaluation: Skin Roughness (% Rated Smooth & Very Smooth)
87.2
90
80
61.6
55
60
55.4
50
41
41
35
40
30
88+
85.1
71.1
70
50
100*
95.9*
100
35
20
20
10
0
% Day 0
% Day 15
% Day 45
Cl1
NCl1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
% Day 90
Control
%Day 120
*CL1 Vs Control at .001
+*NCL1 vs Control at .001
Control: Nano Technology Vehicle
Clinical Evaluation: Skin Hydration
Clinical Evaluation: Skin Hydration
2.5
2.5*
2.4*
2.2
2.1
2
1.9
1.9
1.9*/+
1.9
1.8
2.4
1.5
1
1.5
1.4
1
day 0
1.5
day 15
day 45
CL1
NCL1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
day 90
Control
day 120
*CL1 vs Control at .001
+NCL1 vs Control
Control: Nano Technology Vehicle
Clinical Evaluation: Skin Hydration
Clinical Evaluation: Skin Hydration (% Rated Hydrated or Very Hydrated)
94.9*
100
87.2*
90
100*
97.4*
89.5+
86.8+
86.6+
80
65.4
70
60
60
52.4
45
50
35
40
30
20
10
15.4 15
5
0
% Day 0
% Day 15
% Day 45
Cl1
NCl1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
% Day 90
Control
%Day 120
*CL1 vs NCL1 & Control at .001
+NCL1 vs Control at .001
Control: Nano Technology Vehicle
Clinical Evaluation: Skin Elasticity
Clinical Evaluation: Skin Elasticity
5
4.7*
4.6*
4.5
4.3
4.1
4
4
4
3.9
4
3.8
3.7
3.5
3.5
3.5
3.4
3.4
3.3
3
day 0
day 15
day 45
CL1
NCL1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
day 90
day 120
Control *CL1 vs NCL1 & Control at .001
Control: Nano Technology Vehicle
Clinical Evaluation: Skin Elasticity
Clinical Evaluation: Skin Elasticity (% Rated Good or Excellent)
90
78*
80
70
63.3*
60
47.3*
50
40.7
40
38.1
35
31.4
30.8
27.4
26.8
30
21.8
21.3
20
10
0
% Day 15
% Day 45
Cl1
% Day 90
NCl1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
Control
% Day 120
*CL1 vs NCL1 & Control at .001
Control: Nano Technology Vehicle
Clinical Evaluation: Skin Radiance
Clinical Evaluation: Skin Radiance
2
2*
1.9*
1.8
1.6
1.5
1.5
1.3
1.3
1.5
1.3
1.2
1.1
1
1
0.5
0
day 0
day 15
CL1
day 45
NCL1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
day 90
Control
day 120
*CL1 vs NCL1 & Control at .001
Control: Nano Technology Vehicle
Clinical Evaluation: Skin Radiance
Clinical Evaluation: Skin Radiance (% Rated Radiant or Very Radiant)
100*
100*
94.9
89.2
100
90
75
80
76.9
80
75
78.9
69.2
70
60
59
59+
50
50
50
40
32
30
20
10
0
% Day 0
% Day 15
% Day 45
Cl1
NCl1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
% Day 90
Control
% Day 120
*CL1 vs Control at .001
+NCL1 vs Control at .001
Control: Nano Technology Vehicle
Clinical Evaluation: Smoothing Effect
Clinical Evaluation: Smoothing Effect
2.5
2.1*
2
1.8*
1.5
1.5*
1.5+
1.3+
1
1.1
1.1+
0.9
0.5
0
0.4
0
day 15
0.5
0.1
day 45
CL1
day 90
NCL1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
Control
day 120
*CL1 vs Control at .001
+NCL1 vs Control at
Control: Nano Technology Vehicle
Clinical Evaluation: Smoothing Effect
Clinical Evaluation: Smoothing Effect (% Rated Significant or Very
Significant)
90
79.1*
80
72.3*
70
60
48.7*
50
38.0+
40
28.9+
30
20
10.3
10
10.5
2.6
0
0
0
0
0
% Day 15
% Day 45
Cl1
% Day 90
NCl1
Control
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
% Day 120
*CL1 vs NCL1 & Control at .001
+NCL1 vs Control at .001
Control: Nano Technology Vehicle
Clinical Evaluation: Overall Efficacy
Clinical Evaluation: Overall Efficacy
2.5
2.2*
2
1.9*
1.5
1.5
1.6+
1.3+
1.1
1.1
1
0.8
0.5
0.4
0
0.1
0.05
day 15
0.4
day 45
CL1
day 90
NCL1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
Control
day 120
*CL1 vs Control at .001
+NCL1 vs Control at .001
Control: Nano Technology Vehicle
Clinical Evaluation: Overall Efficacy
Clinical Evaluation: Overall Efficacy (% Rated Good or
Excellent)
100
93.3*
90
76*
80
70
60
48.7
50
35+
40
27.5+
30
20
10
18.4
12.8
5.1
0
0
0
0
0
% day 15
% day 45
Cl1
% day 90
NCl1
Control
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
% day 120
*CL1 vs NCl1 & Control at .001
+NCL1 vs Control at .001
Control: Nano Technology Vehicle
Clinical Evaluation: Tolerance
Clinical Evaluation: Local Tolerance (% Rated Excellent)
100
100
100
100
100
100
100
100
100
100
90
80
70
60
50
40
30
20
10
0
day 15
day 45
CL1
NCL1
day 90
Control
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
Control: Nano Technology Vehicle
Blinded Subjective Assessments
Subjective Evaluation: Wrinkle Improvement
Subjective: Wrinkle Im provem ent (% Rated Good or Excellent)
60
50.5*
47.4
50
40
40
32.4
28
30
25
20
20
10
10
10
0
% day 15
% day 45
Cl1
NCl1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
% day 90
Control
*CL1 vs Control
Control: Nano Technology Vehicle
Subjective Evaluation: Elasticity and Tightness
Subjective: Elasticity & Tightness
2
1.5
1.4*
1.5
1.3
1.1
1
1
0.8
0.6
0.5
0
day 15
day 45
CL1
NCL1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
day 90
Control
*CL1 vs Control at .05
Control: Nano Technology Vehicle
Subjective Evaluation: Elasticity and Tightness
Subjective: Elasticity & Tightness (% Rated Good or Excellent )
48.7*
50
43.6*
45
36.9
40
35
30
26.5
25
20
17.9
19
25
17
16
15
10
5
0
% Day 15
% Day 45
Cl1
NCl1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
% Day 90
Control
* CL1 vs Control at .05
Control: Nano Technology Vehicle
Subjective Evaluation: Texture Improvement
Subjective: Skin Texture
1.9*
2
1.6*
1.4
1.5
1
1.2
0.9
1.1
0.9
0.7
0.5
0
day 15
day 45
CL1
NCL1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
day 90
Control
*CL1 vs Control at .05
Control: Nano Technology Vehicle
Subjective Evaluation: Texture Improvement
Subjective: Skin Texture (% Rated Good or Excellent)
80
71.8*
70
60
51.3*
50
50
40
30
20
24.1
23
15.4
25
21
15
10
0
% Day 15
% Day 45
Cl1
NCl1
Control
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
% Day 90
*CL1 vs. NCL1 & Control
at .05
Control: Nano Technology Vehicle
Subjective Evaluation: Skin Hydration Improvement
Subjective: Skin Hydration
2
1.8
1.7*
1.75
1.5
1.5
1.3
1.25
1.2
1.1
1
1
day 15
day 45
CL1
NCL1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
day 90
Control
*CL1 vs Control at .05
Control: Nano Technology Vehicle
Subjective Evaluation: Skin Hydration Improvement
Subjective: Skin Hydration (% Rated Good or Excellent)
80
71.8*
66.6*
70
60
52.6
50
40
42.1
30.8
30
26.4
30
20
55
18
10
0
% Day 15
% Day 45
% Day 90
*CL1 vs NCL1 & Control at .05
*CL1 vs NCL1 & Control at .05
Cl1
NCl1
Control
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
Control: Nano Technology Vehicle
Subjective Evaluation: Global Appearance Improvement
Subjective: Global Skin Appearance Improvement
1.8*
2
1.5*
1.5
1
1.2
1.1
1.1
1
0.8
0.7
0.7
0.5
0
day 15
day 45
CL1
NCL1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
day 90
Control
*CL1 vs Control at .05
Control: Nano Technology Vehicle
Subjective Evaluation: Global Appearance Improvement
Subjective: Global Skin Appearance (% Rated Good or Excellent)
70
61.5*
60
51.3*
50
42.1
40
30
20
34.2
23.1
30
20
12.8
10.5
10
0
% Day 15
% Day 45
Cl1
NCl1
Control
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
% Day 90
*Cl1 vs Control at .001
Control: Nano Technology Vehicle
Subjective Evaluation: Overall Efficacy
Subjective Overall Efficacy of the Product
2
1.9
1.8*
1.75
1.6
1.5
1.5
1.5
1.4
1.3
1.25
1.1
1
day 15
day 45
CL1
NCL1
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
day 90
Control
*CL1 vs Control at .05
Control: Nano Technology Vehicle
Subjective Evaluation: Overall Efficacy
Subjective: Product Efficacy (% Rated Good or Excellent)
80
70*
67*
70
60
50
40
43.6
50
47.4
45
45
35.9
26.5
30
20
10
0
% Day 15
% Day 45
% Day 90
*Cl1 vs Control at .05
Cl1
NCl1
Control
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA
Control: Nano Technology Vehicle
Product Qualities
Assessment of Product
Smell
Subjective: Smell of Product (% Rated Satisfactory & Very Satisfactory)
100
100
95
92.5
95
95
92.1
86.9
90
80
74.4
76.9
day 45
day 90
70
60
50
40
30
20
10
0
day 15
CL1
NCL1
Control
Assessment of Product
Color
Subjective: Color of Product (% Rated Satisfactory & Very Satisfactory)
100
97
100
100
100
95
89.5
86.9
90
82.1
82
day 45
day 90
80
70
60
50
40
30
20
10
0
day 15
CL1
NCL1
Control
Assessment of Product
Texture
Subjective: Texture of Product (% Rated Satisfactory & Very Satisfactory)
100
100
92.1
95
100
94.8
84.7
90
100
94.8
82.1
80
70
60
50
40
30
20
10
0
day 15
day 45
CL1
NCL1
day 90
Control
Assessment of Product
Easiness of Application
Easiness of Application of the Product (% Rated Satisfactory & Very
Satisfactory)
99
100
100
100
98
92
90
97.4
100
92.3
90
80
70
60
50
40
30
20
10
0
day 15
day 45
CL1
NCL1
day 90
Control
Assessment of Product
Penetration
Easiness of Penetration of the Product (% Rated Satisfactory & Very
Satisfactory)
100
100
91
92.5
97.4
100
92.3
94.8
100
92.3
90
80
70
60
50
40
30
20
10
0
day 15
day 45
CL1
NCL1
day 90
Control
Assessment of Product
Overall Qualities of the Cream
Subjective: Overall Assessment of Product (% Rated Satisfactory & Very
Satisfactory)
100
90
90
80
95
86.9
86.9
80
76
76.9
70
69.2
70
60
50
40
30
20
10
0
day 15
day 45
CL1
NCL1
day 90
Control
Topical Hyaluronic Acid (HA)
90 Day Results Summary I

Blinded Investigator evaluations showed highly
statistically significant improvement using the topical
crosslinked HA (Restylane) over time and vs the non cross
linked and vehicle in Skin Roughness, Hydration,
Elasticity, Radiance, Smoothing Effect and Overall
Efficacy. Most dramatic differences with Smoothing
Effect and Overall Efficacy
 Blinded subjective evaluations showed highly statistically
significant improvement using the topical crosslinked HA
(Restylane) over time and vs the non cross linked and
vehicle in, Hydration, Elasticity and tightness, Texture
improvement,, Global Appearance Improvement and
Overall Efficacy
.
Topical Hyaluronic Acid (HA)
90 Day Results Summary II
 Overall
the non crosslinked HA showed better
efficiency than the vehicle but was inferior to the
crosslinked HA
 Wrinkle evaluation using Goldman-Rao scale was
to course a measurement to show statistical
differences but clinical photos showed significant
improvement using the crosslinked HA
 Tolerance: 97 out of 100 patients finished the
trial. No dropout because of tolerance issues. No
significant complaints of irritation, dryness,
itching or redness. No investigator observed
.
untoward effects. Subjects liked the product
texture, color, penetration, and ease of application
Topical Hyaluronic Acid (HA)
Washout Results Summary
 Blinded
Investigator evaluations showed
highly statistically significant continued
improvement after 30 day washout using the
topical crosslinked HA (Restylane) vs the non
cross linked and vehicle which overall lost
significant ground on improvement
 Dramatic clinical improvement after washout
period in categories of skin roughness,
smoothing effect and overall efficiency
.
Topical Hyaluronic Acid (HA)
Discussion

Topical crosslinked HA (Restylane) and non crosslinked HA appears
penetrate the skin using the unique Ionic Nano Particle Technology
(InParT) delivery system
 Topical crosslinked HA (Restylane) and to a lesser extent non
crosslinked HA appear to have significant aesthetic enhancement
effect in this double blind vehicle controlled trial in virtually every
category of blinded investigator evaluations and subjective
evaluations as well as in clinical photographic assessments
 The benefits of the topical crosslinked HA (Restylane) continue to
improve even when the product is discontinued perhaps indicating a
long term benefit to the skin brought forth by collagen remodeling
 Early discussion with regulatory attorneys indicates that topical
crosslinked HA probably does not need an NDA and can be sold as a
cosmecutical
.
90 Day Photos
49
33
33
BEFORE
BEFORE
BEFORE
BEFORE
BEFORE
AFTER
NTL4: The Next Generation Topical Anesthetic
Optimized 4% Topical Lidocaine in a Unique Nano
Technology Delivery System
Results of Clinical Trials Comparing NTL4 to LMX4
Protocols N°
10025
10025.1
Center for Clinical and Cosmetic Research (CCCR), Aventura, Florida
Mark S. Nestor, M.D., Ph.D.
Disclosure





NTL4 is an experimental topical Anesthetic owned by
Innovatech, Inc.
LMX4 is a commercially available topical anesthetic
owned by Ferndale Laboratories
Clinical studies results in this presentation are
preliminary
Studies preformed at CCCR in Aventura, Florida and
Manhattan Beach, California. Mark S. Nestor, M.D.,
Ph.D., Principle Investigator, Glynis Ablon, M.D., Co
Investigator
Funding provided by a Research Grant from
Innovatech, Inc.
NTL4

NTL4 is a unique 4% Lidocaine TA based on the INParT drug
delivery system
 The INParT drug delivery system allows for rapid and
efficient transfer of the Lidocaine through the stratum
cornenum, epidermis and dermis to the sensory nerves
 4% lidocaine is ideal because of it OTC FDA indication
 Clinical trails were conducted to test efficacy and safety of
NTL4 as a TA in patients receiving Restylane injections in the
NLF. The trails utilized LMX4 (the market leader in
commercially available 4% lidocaine) in the contra lateral
NLF as an active control
 The initial trial investigated the efficacy and safety comparing
a 20 minute application of both products
 The second trial accessed early onset efficacy at 5, 10, and 15
minute application of both products
CCCR Protocol 10025
Double Blind, Randomized, Split-Face Study to
Evaluate the Efficacy, Safety and Subject
Satisfaction of Pain Management Utilizing NTL4
(Topical 4% Lidocaine in a Novel Nano
Technology Delivery System) vs. LMX 4 (4%
Lidocaine cream) During and After Restylane®
Dermal Filler Injections for the Correction of
Nasolabial Folds
Study Design: Protocol 10025






Two-center, randomized, split-face, double-blind pilot trial to
evaluate the effectiveness of a test product NTL4 versus L-MX4® topical anesthetic immediately post, one and three hours
after Restylane® injections in the NLF.
2-day study
30 patients total for 2 sites randomized left and right to NLT4
or LMX4, respectively, randomly applied (20 second massage)
to each NLF for 20 minutes and removed
Investigator and patient assessments completed at screening
/injection immediately upon injection, at 1 hour and 3 hours at
visit 1
Follow-up assessments completed at Visit 2 (next day)
AE and concomitant medication review / update at each visit
AE, adverse event.
Results Summary: Protocol 10025





Subjective mean VAS scores for the 30 subjects indicated
significantly less pain upon injection (p=0.04), one hour after
injection (p< 0.01) and trend at 3 hours (p=0.06) favoring NTL4
over LMX4
Subjective assessment of level of pain indicated clear but not
significant trend favoring NTL4 over LMX4
Subjects preference of topical anesthetic significantly favored
NTL4 over LMX4 (p=0.002)
Blinded investigator assessment of pain indicated significantly
less pain on the NTL4 treated vs. LMX4 treated side (p=0.002)
Blinded investigators overall satisfaction (adequate anesthesia)
significantly favored NTL4 over LMX4 (p< 0.001)
Results Summary: Protocol 10025
 AE’s
were all classified as minor and
included tenderness, bruising and edema
all of which were considered to be related
to the Restylane injections
 There were no apparent differences in the
injection related AE’s for either NTL4 or
LMX4
CCCR Protocol 10025.1
Double Blind, Randomized, Split-Face
Study to Evaluate the Onset of Topical
4% Lidocaine in a Novel Nano
Technology Delivery System vs. LMX 4
(4% Lidocaine cream) During and
After Restylane® Dermal Filler
Injections for the Correction of
Nasolabial Folds
Study Design: Protocol 10025.1







Two-center, randomized, split-face, double-blind pilot trial to
evaluate the effectiveness of a test product NTL4 versus L-MX4® topical anesthetic immediately post, one and three hours
after Restylane® injections in the NLF.
2-day study
20 patients total for 2 sites randomized left and right to NLT4
or LMX4, respectively (30 second massage)
3 group randomization for onset of effectiveness: 15, 10 and 5
minute duration of topical cream prior to injection
Investigator and patient assessments completed at
screening/injection Immediately upon injection, at 1 hour and 3
hours at Visit 1
Follow-up assessments completed at Visit 2 (next day)
AE and concomitant medication review / update at each visit
AE, adverse event.
Results Summary I: Protocol 10025.1

Subjective mean VAS scores for the 20 subjects
(combined early onset) indicated significantly less pain
upon injection (p<0.001), with trends at one hour after
injection and trend at 3 hours favoring NTL4 over
LMX4. VAS immediate injection score lower for
NTL4 in early onset trial vs original 20 minute trial
(1.57 vs 1.99) but higher for the LMX4 (3.86 vs 3.02)
.Mean Individual onset groups: significantly less pain
favoring NTL4 over LMX4 for 15 minute and 5
minute incubations (p=0.04) with trend favoring NTL4
at 10 minutes. Trends favoring NTL4 at one and three
hours in all groups
Results Summary II: Protocol 10025.1

Subjective assessment for the 20 subjects (combined early onset) of
level of pain indicated significant less pain on NTL4 over LMX4
(p<0.001). Individual onset groups: significantly less pain favoring
NTL4 over LMX4 for 15 minute and 5 minute incubations (p=0.01,
p=0.006) with trend favoring NTL4 at 10 minutes.
 Subjects preference of topical anesthetic for the 20 subjects
(combined early onset) significantly favored NTL4 over LMX4
(p=0.002). Individual onset groups: significant preference favoring
NTL4 over LMX4 for 15 minute 10 minute and 5 minute incubations
(p=0.001, p= 0.05, p=0.02)
 Blinded investigator assessment of pain for the 20 subjects (combined
early onset) indicated significantly less pain on the NTL4 treated vs.
LMX4 treated side (p=0.001) Individual onset groups: significantly
less pain favoring NTL4 over LMX4 for 15 minute (p=0.02) with
trends favoring NTL4 for the 10 minute and 5 minute incubations
Results Summary III: Protocol 10025.1

Blinded investigators overall satisfaction (adequate
anesthesia) for the 20 subjects (combined early onset)
significantly favored NTL4 over LMX4 (p<0.001).
Individual onset groups: significant preference
favoring NTL4 over LMX4 for 15 minute 10 minute
and 5 minute incubations (p= 0.05)
 AE’s were all classified as minor and included
tenderness, bruising and edema all of which were
considered to be related to the Restylane injections.
One patient (15 minute) demonstrated erythema and
edema lasting 4 days, initially bilateral and then
unilateral (NTL4 side). Cleared with topical cortisone.
Thought to be reaction to Lidocaine.
Efficacy Results: Subjective VAS
Early Onset (5 Minutes) (N=6)
5
4
3
NTL4
LMX4
2
1
0
Immediate
1 Hour
3 Hour
X Axis: Time After Injection
Y Axis: VAS Scale
N=6
N=6
N=6
p=0.045
p=0.309
p=0.643
d=0.61 (Large)
d=0.27 (Small)
Subjective Level of Pain
Early Onset (5 Minutes) (N=6)
Bar Chart
Subject_Level_of_Pain
Count
4
No Pain
Minimal Pain
Mild Pain
Moderate Pain
3
2
1
0
NTL4
LMX4
Product_Randomization
P=0.079
Subject Satisfaction Data: Overall Preference
Early Onset (5 Minutes) (N=6)
6
5
4
3
Subject Preference
2
1
0
NTL4
LMX4
Preference Rates:
NTL4 = 83% (5/6)
LMX4 = 16% (1/6)
No Preference = 0% (0/8)
No
Preference
P=0.02
Blinded Investigator’s Evaluation of Pain
Early Onset (5 Minutes) (N=6)
Bar Chart
Subject_Level_of_Pain
4
No Pain
Minimal Pain
Mild Pain
Count
3
2
1
0
NTL4
LMX4
Product_Randomization
P=0.076
VAS Comparison: Onset
Immediate Post Injection
5
4
3
NTL4
LMX4
2
1
0
20 minutes 15 minutes 10 minutes 5 minutes
N=30
p=0.044
X Axis: Duration of Application
Y Axis: VAS Scale
N=6
p=0.004
N=8
p=0.068
d=0.98 (Large)
N=6
p=0.045
Discussion I



Trails compared subjective and blinded investigator assessment
pain, as well as preference following Restylane injections in the
NLF comparing a novel 4 % lidocaine in nano technology
delivery system (NTL4) to commercially available LMX4
Results indicate that NTL4 is significantly superior to LMX4
according to blinded subjective bilateral comparisons and
blinded investigator observations. Results consistent at one hour
and three hours after injection and is related to both half life of
lidocaine and decreased initial pain
NTL4 appears to have significant efficiency with extremely
short incubation (15,10 and 5 minutes) after 30 second massage
application. Variations in significance of individual onset
groups secondary to small n in each group. Differences between
initial and early onset study (apparent enhanced effect of NTL4
may be due to 30 vs 20 second application massage)
Discussion II






AE’s mild and appear associated with injections except for one
subject. Erythema and edema started bilaterally and continued in
NTL4 treatment side. Probable cause is lidocaine topical sensitivity.
NTL4 show significant promise as a next generation topical
anesthetic having significantly enhanced effect and early onset ability
Nano technology allows for enhanced rapid penetration of lidocaine
through the stratum corneum, epidermis and dermis to the sensory
nerves
4% lidocaine allows for OTC status: both as a physician used
(dispensed) and general consumer use
Short incubation times (early onset) will be very attractive to
dermatologists and pediatricians
Commercial launch of OTC within months (just need stability testing)
NTL4 (4% Topical Lidocaine
Anesthetic Utilizing a Novel Micelle
Nano Technology Delivery System):
Anesthetic Properties and Lidocaine
Toxicity
Mark S. Nestor, M.D., Ph.D.
Glynis R. Ablon, M.D.
Center for Clinical and Cosmetic Research
Introduction I
•
•
•
A recent study showed that NTL4 (Innovatec,
Inc), a new topical nanotechnology lidocaine
preparation, was significantly more effective than
L.M.X.4® (Ferndale laboratories), a
commercially available topical lidocaine
preparation at decreasing pain upon injection of
Restylane in the nasolabial folds.
The preparation worked in as little as 5 minutes.
Because of the improved capabilities of NTL4
this study will evaluate absorption and potential
systemic effects of lidocaine.
Introduction II
 The
objective of this clinical study is the
detection of lidocaine levels in blood after the
application of up to 60 grams of NTL4 under
occlusion for 60 minutes on the face, abdomen
or thighs of ten study participants.
 Additionally a needle stick test using a
subjective VAS pain scale will be used to
determine efficacy of the NTL4. Analysis will
include comparison of mean VAS scores for
the treated and non treated areas.
Methods I
•
•
•
•
10 subjects between 25 and 65
Blood samples (approximately 3-5cc each) were drawn
from each participant at baseline (before NTL4 cream is
applied*) following central laboratory instructions.
NTL4 cream was applied (30 grams) on the whole face of
4 volunteers. Three volunteers had 60 grams of the cream
applied on a 600 cm2 area on their abdomen and the
remaining three on their thighs under plastic wrap
occlusion
The cream was applied on different areas of the body to
determine differences in absorption.
Methods II




NTL4 cream was left on the area for at least 60 minutes. After
the 60 minutes, the cream was completely removed using
tongue depressors and lint-free wipes as well as alcohol wipes.
A second blood sample was taken at this time.
Blood samples were taken again at 2, 6 and 24 hours post
initial application of the anesthetic cream
The VAS (Visual Analog Pain) scale was used to determine
the effectiveness of the topical anesthetic
The subject was asked to evaluate the pain experienced at
needle stick in the area covered by the topical anesthetic as
well as an untreated adjacent area, by responding to a pain
intensity scale.
Results
Results I



Patients’ lab results were negative for any level of lidocaine or
lidocaine metabolites.
No neurological, cardiovascular, or gastrointestinal indications
of lidocaine toxicity were observed.
In 100% of the patients raw scores of the VAS showed that
patients reported less pain upon needle stick on the treated area
when compared to the non-treated area. Table 1 illustrates
descriptive data for number of patients, mean scores, and
standard deviations for VAS scores on treated and non-treated
areas
Results II
Table 1.
VAS Scores
N
M
SD
Treated
Non Treated
10
10
1.1
4.9
.95
2.46
A one-way analysis of variance was used to test mean differences between the
2 areas. Results indicated that a significant difference exists between the
treated and non-treated areas (F [1,18] = 21.0, p<.001).
Discussion
 NTL4
is an extremely effective topical
anesthetic
 Moderate amounts of NTL4 (up to 60 grams
under plastic wrap occlusion) showed no blood
levels of lidocaine or metabolites
 Dramatic reduction in VAS pain scale to
needle stick
 NTL4 safe and effective topical anesthetic
Topical BP Combination
Acne
InParT Drug Delivery System
Topical BP: Acne I
 BP
is one of the most effective and enduring
acne treatments
 BP dramatically reduces bacteria (p. acnes)
without causing bacterial resistance and in fact
can reduce bacterial resistance if this has
arisen from antibiotic therapy.
 Reduces the number of yeasts on the skin
surface.
 BP is an oxidizing agent and is keratolytic and
comedolytic i.e. it reduces the number of
comedones
 Anti-inflammatory action
InParT Drug Delivery System
Topical BP: Acne II

Insoluble BP causes skin to stain clothes need better
alternatives
 Prescription strength BP is a Desi Drug. Rapid FDA
approval but FDA transitioning to OTC designation
 OTC BP is a tremendous market opportunity
 The active ingredient in Proactiv product is BP:
$500,000,000 in annual sales
 Total market OTC BP is approximately
$2,000,000,000
 Low dose BP in InParT delivery can be more
effective with fewer side effects (irritation and
dryness)
Topical BP: Acne
Clinical Model
 InParT
can theoretically maximize penetration
and delivery of BP
 Improved efficiency
 Minimal PB remains on skin surface to lighten
skin and stain clothing
 Delivery system can also work with BP
combination compounds
Topical BP: Acne
Pilot Clinical Study
 Objective
To evaluate the efficacy of the
novel INParT topical (BP 3.5%, 1.5%
salicylic acid and 3% Hydrogen peroxide)
in moderate to severe acne vulgaris
 Design open-label treatment phase,
randomized, parallel-group maintenance
phase in comparison with VC (placebo
treatment).
Topical BP: Acne
Pilot Clinical Study




Subjects: 26 patients (male/female 14/12) Duration acne was on
average 2-3 years
Trial Duration: 8 week Twice a day
Main Outcome Measures Overall disease severity, global
improvement, and lesion counts. Patients were seen at baseline,
defined as the visit when treatment was initiated, and again at 2, 4,
8 weeks of treatment. Lesion count, global response and
photographs
The global response to treatment scores were assessed by
comparing the patient's condition with baseline photographs and
then were graded from 0 to 6 as follows:







0, completely cleared;
1, approximately 90% improved;
2, approximately 75% improved;
3, approximately 50% improved;
4, approximately 25% improved;
5, no change; and
6, exacerbation.
Topical BP: Acne
Pilot Clinical Study
 Results:


After 8 weeks or less treatment the mean
reductions from baseline in non inflammatory
and inflammatory lesion count, were 66%
and 69% with this novel formulation in
comparison with placebo where improvement
was 3.7% and 5.2%
At week 4, more than 80% of patients had
maintained a 50% or greater global
improvement from baseline, and more than
40% had maintained a 75% or greater global
improvement.
Topical BP: Acne
Pilot Clinical Study





Results:
Overall disease severity score mean ± SD 3.7±1.7
Mean percentage (%) change in papules and pustules
Baseline week 1 week 2 week 4 week 6 week 8
0
7.5
15.1
27.7
40.1
56.3
Incident of >50% global improvement from baseline 21/26
 Incident of >75% global improvement from baseline 14/26
 % change non-inflammatory lesions counts 64±22.2
 % change inflammatory lesions counts
67±27.3
Topical BP: Acne
Pilot Clinical Study
 AEs:
There were no SAEs observed
during this study over period
 Most subjects reported excess dryness
(24/26).
 Redness and peeling at the site of
application (9/26).
 Burning sensation when they applied the
treatment for the first time (5/26), faded
after 5-7 days of the treatment.
Clinical Photographs
Baseline
4 weeks
Clinical Photographs
Baseline
6 weeks
Clinical Photographs
Baseline
3 weeks
6 weeks
Clinical Photographs
Baseline
3 weeks
6 weeks
Topical Botulinum
Neurotoxin
Hyperhidrosis
Introduction I

Hyperhidrosis is considered a chronic disorder
that is characterized by excessive sweating in the
axilla, palm, soles, or face
 Injection of abobotulinumtoxin, Botox is
approved by the FDA for the treatment of severe
primary axillary hyperhidrosis but many patients
do not tolerate the extensive injections
 Additionally a large market exists for individuals
who would like to “cosmetically” stop
perspiration for an extended period of time
without the need for injections
Introduction II
 The
InParT Transdermal Delivery System has
been shown to have significant efficacy for
passively transporting botulinum toxin both for
aesthetic benefits as well as hyperhidrosis
 Multiple dose trials outside US
 In US pilot study, 3 different FDA approved
toxins will be utilized in single dose treatment
regime to determine initial efficacy of the
delivery system
InParT Drug Delivery System
Topical BoNTA: Hyperhidrosis
 Need
for a topical neurotoxin for
Hyperhidrosis


Painless application
Needle phobia
 Coupled
with application device for in office
procedure
 Allergan owns patent (2014) but can be used
off label
Topical BoNTA: Hyperhidrosis
Clinical Model

The stabilized cream is applied topically onto the skin
containing fixed (exact) amount of the Toxin
 The nano-spheres helps penetrate the skin layers with
the aid of absorption enhancers and releases the
stabilized toxin into the deep layers of the skin
 Toxin diffuses into the eccrine glands (Smooth
muscles) inhibiting the release of acetylcholine and
reducing sweat production
Topical BoNTA: Hyperhidrosis
Pilot Clinical Study I*

Prospective open label study axillary and palmer hyperhidrosis
 24 subjects (18 – 59)
 Starch Iodine and Gravimetric tests
 Botulinum toxin type A gel is applied, twice a day for 1 weeks, 6
units per day. (42 units at the end of the study).
 Weekly follow up for 12-16 weeks, with picture records,
colorimetric and gravimetric test at week 4 and at the end of the
study.
 Adverse effects were recorded.
 Patients answered a questionnaire of satisfaction at the end of the
study.
*Rogelio J, Morales O: HYPERHIDROSIS TREATMENT WITH TOPIC
BOTULIN TOXIN TYPE A GEL Submitted
.
Topical BoNTA: Hyperhidrosis
Pilot Clinical Study II*



Analysis Friedman Test:
mg/min: 79% reduction at
12 weeks for all areas
P<0.0002
Analysis Friedman Test:
cm2: 89% reduction at 12
weeks for all areas P<0.004
High Satisfaction Low AE’s
mostly dryness
*Rogelio J, Morales O: HYPERHIDROSIS TREATMENT WITH TOPIC
BOTULIN TOXIN TYPE A GEL Submitted
.
Hyperhidrosis; Before and After ( at week 16)
Hyperhidrosis; Before and After ( at week 16)
Topical Botulinium Toxin
in the Treatment of
Hyperhydrosis
Mark S. Nestor, M.D., Ph.D.
Glynis R. Ablon, M.D.
Center for Clinical and Cosmetic Research
Confidential Preliminary Data
Methods


15 subjects 2 US sites
Baseline axillary hyperhydrosis as defined by gravimetric
test (>50 mg sweat per 5 minutes)
 No antiperspirant or deodorant for 3 days before and during
trail
 One axilla single topical treatment:
•
•
•



5 subjects: 300 units of Dysport in InParT transport system
5 subjects: 100 units of Botox in InParT transport system
5 subjects: 2500 units of Myobloc in InParT transport system
Contralateral axilla: InParT transport system alone
Under occlusion for 60 minutes
Evaluated at 15 and 30 days with gravimetric and starch
iodine
Results
Note: Relative change from control similar in Botox group
Patient 1

Baseline hyperhydrosis as defined by gravimetric
test (>50 mg sweat per 5 minutes)
 No antiperspirant or deodorant for 3 days before
and during trail
 One axilla single topical treatment with 300 units
of Dysport in unique InParT transport system
 Contralateral axilla treated with InParT transport
system alone
 Both under occlusion for 60 minutes
Patient 1
Baseline
Control
Topical Dysport
Gravimetric Tests
129.0mg
102.9 mg
Patient 1
Day 8
Control
Topical Dysport
Gravimetric Tests
120.2 mg
13.7 mg
Patient 1
Day 8
Control
Topical Dysport
Gravimetric Tests
120.2 mg
13.7 mg
Patient 1
Day 14
Control
Topical Dysport
Gravimetric Tests
128.1 mg
14.0mg
Patient 1
Day 14
Control
Topical Dysport
Gravimetric Tests
128.1 mg
14.0 mg
Patient 1
Day 30
Control
Topical Dysport
Gravimetric Tests
100.9 mg
26.3mg
Patient 1
Day 30
Control
Topical Dysport
Gravimetric Tests
100.9 mg
26.3mg
Discussion

Pilot study with 3 toxins (Botox, Dysport and
Myobloc) to determine effect of a single low dose
topical application
 All three topical toxins showed effect
 Overall a 20% decrease over control with 100%
of subjects having lower amounts of perspiration
on the treated side at day 15 and 80% at day 30
 Individual subjects had up to 90% reduction at
day 15 and 80% at day 30
 Need further clinical trails to optimize dosing and
application
InParT Drug Delivery System
Future Applications
 Hyperpigmentation and
 Psoriasis
 Rosacea
 Onychomycosis
 Xerosis
 Cosmeutical
 Hair
Growth
Melasma
InParT Drug Delivery System
Opportunities
 Partnership vs. License Technology
 Enhance existing topical toxin
 HA
 Lidocaine
 Hydroquinone
 Collaborative
effort
 Strategic Investment
 Sale