NTL4
The Next Generation Topical Anesthetic
Optimized Topical Lidocaine 4% in a Unique Nano
Technology Delivery System
Res...
 NTL4 is an experimental topical Anesthetic owned by
Innovatech, Inc.
 LMX4 is a commercially available topical anesthet...
 The successful reduction of pain is one of the primary
goals of medical care.
 The medical management of pain encompass...
 TA are classified as RX, OTC or pharmacy compounded
medications and contain a variety of ingredients from benzocaine to
...
Topical Drug Delivery
 The skin is a formidable barrier against
environmental assaults as well as topical drug
delivery
...
InParT Drug Delivery System
Ionic Nano Particle Technology I
Novel, commercially viable trans
dermal non-invasive drug de...
InParT Drug Delivery System
Ionic Nano Particle Technology II
 Nano particles are made from combinations of
micelles (sur...
InParT Drug Delivery System
Ionic Nano Particle Technology III
 INParT technology is highly adaptable to
most high molecu...
SEM-Photograph- 250x SEM-Photograph- 1000x
 NTL4 is a unique 4% lidocaine TA based on the INParT
drug delivery system
 The INParT drug delivery system allows for r...
CCCR Protocol 10025
Double Blind, Randomized, Split-Face Study
to Evaluate the Efficacy, Safety and Subject
Satisfaction o...
Study Design: Protocol 10025
 Two-center, randomized, split-face, double-blind pilot trial to evaluate
the effectiveness ...
Treatment
 Topical NTL4 and LMX4
were randomly applied (20
second massage) to each
NLF for 20 minutes and
removed
 Resty...
Patient Assessments & Scale
 Upon first needle stick of each of the NLF injections, the patient
assessed the amount of pa...
Patient Assessments & Scale
 1 Hour following injection, subjects were asked to complete
a satisfaction survey addressing...
Investigator Assessments
 Upon injection, investigator completed a
immediate assessment to evaluate severity of
the patie...
Investigator Scale
 The severity of the patient’s perceived pain during the
procedure was scored on a 4-point grading sys...
Results
Efficacy Results: Subjective VAS
Group Statistics
30 1.997 1.5736 .2873
30 3.087 2.4329 .4442
30 .217 .3086 .0563
30 .747 ...
Efficacy Results: Subjective VAS
N=30 N=30 N=30
p=0.04 p=0.01 p=0.06
d=0.48 (Medium)
X Axis: Time After Injection
Y Axis: ...
Subject Satisfaction Data
Subjective Level of Pain
Randomization * Subject_Level_of_Pain Crosstabulation
2 18 7 2 1 30
1.0...
Subject Satisfaction Data
Subjective Level of Pain
P=0.22
(B) LMX4(A) NTL4
Randomization
20
15
10
5
0
Count
Severe Pain
Mo...
Subject Satisfaction Data
Overall Preference
Product_Randomization * Preference Crosstabulation
18 6 6 30
12.0 12.0 6.0 30...
Subject Satisfaction Data
Overall Preference
System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=30...
Blinded Investigator’s Evaluation
of Pain
Randomization * Investigator_Rating Crosstabulation
11 17 2 0 30
6.0 17.5 5.0 1....
Blinded Investigator’s Evaluation
of Pain
System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
P...
Blinded Investigator’s Overall
Satisfaction of Topical Anesthetic
System Organ Class
Preferred Term
Placebo
n=100
Dysport ...
Blinded Investigator’s Overall
Satisfaction of Topical Anesthetic
Preferred Term, n (%) Placebo
n=100
Dysport 50 U
n=200
T...
Results: AE’s
 AE’s were all classified as minor and
included tenderness, bruising and
edema all of which were considered...
Results Summary: Protocol 10025
 Subjective mean VAS scores for the 30 subjects indicated
significantly less pain upon in...
Results Summary: Protocol 10025
 AE’s were all classified as minor and
included tenderness, bruising and
edema all of whi...
CCCR Protocol 10025.1
Double Blind, Randomized, Split-
Face Study to Evaluate the Onset
of Topical 4% Lidocaine in a Novel...
Study Design: Protocol 10025.1
 Two-center, randomized, split-face, double-blind pilot trial to evaluate
the onset and ef...
Treatment
 Topical NTL4 and LMX4
were randomly applied (30
second massage) to each
NLF for 15, 10 or 5 minutes
and remove...
Patient Assessments & Scale
 Upon first needle stick of each of the NLF injections, the patient
assessed the amount of pa...
Patient Assessments & Scale
 1 Hour following injection, subjects were asked to complete
a satisfaction survey addressing...
Investigator Assessments
 Upon injection, investigator completed a
immediate assessment to evaluate severity of
the patie...
Investigator Scale
 The severity of the patient’s perceived pain during the
procedure was scored on a 4-point grading sys...
Results
Efficacy Results: Subjective VAS
Early Onset Groups Combined (N=20)
Group Statistics
20 1.520 1.0191 .2279
20 3.860 2.2763...
Efficacy Results: Subjective VAS
Early Onset Groups Combined (N=20)
N=20 N=20 N=20
p<0.001 p=0.242 p=0.161
d=0.37 d=0.45 (...
Efficacy Results: Subjective VAS
Early Onset (15 Minutes) (N=6)
Group Statistics
6 1.917 1.1873 .4847
6 4.667 1.3721 .5602...
Efficacy Results: Subjective VAS
Early Onset (15 Minutes) (N=6)
N=6 N=6 N=6
p<0.004 p=0.085 p=0.22
d=1.1 (Large) d=0.75 (L...
Efficacy Results: Subjective VAS
Early Onset (10 Minutes) (N=8)
Group Statistics
8 1.075 .8311 .2938
8 3.000 2.6306 .9301
...
Efficacy Results: Subjective VAS
Early Onset (10 Minutes) (N=8)
N=8 N=8 N=8
p=0.068 p=0.279 p=0.724
d=0.98 (Large) d=0.56 ...
Efficacy Results: Subjective VAS
Early Onset (5 Minutes) (N=6)
Group Statistics
6 1.717 1.0088 .4118
6 4.200 2.4528 1.0013...
Efficacy Results: Subjective VAS
Early Onset (5 Minutes) (N=6)
N=6 N=6 N=6
p=0.045 p=0.309 p=0.643
d=0.61 (Large) d=0.27 (...
Subjective Level of Pain
Early Onset Groups Combined
(N=20)
Product_Randomization * Subject_Level_of_Pain Crosstabulation
...
Subjective Level of Pain
Early Onset Groups Combined (N=20)
P<0.001
LMX4NTL4
Product_Randomization
14
12
10
8
6
4
2
0
Coun...
Subjective Level of Pain
Early Onset (15 Minutes) (N=6)
Product_Randomization * Subject_Level_of_Pain Crosstabulation
5 0 ...
Subjective Level of Pain
Early Onset (15 Minutes) (N=6)
P=0.01
LMX4NTL4
Product_Randomization
5
4
3
2
1
0
Count
Moderate P...
Subjective Level of Pain
Early Onset (10 Minutes) (N=8)
Product_Randomization * Subject_Level_of_Pain Crosstabulation
1 6 ...
Subjective Level of Pain
Early Onset (10 Minutes) (N=8)
P=0.006
LMX4NTL4
Product_Randomization
7
6
5
4
3
2
1
0
Count
Sever...
Subjective Level of Pain
Early Onset (5 Minutes) (N=6)
System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
...
Subjective Level of Pain
Early Onset (5 Minutes) (N=6)
Preferred Term, n (%) Placebo
n=100
Dysport 50 U
n=200
Total
N=300
...
Subject Satisfaction Data: Overall Preference
Early Onset Groups Combined (N=20)
Product_Randomization * Preference Crosst...
Subject Satisfaction Data: Overall Preference
Early Onset Groups Combined (N=20)
System Organ Class
Preferred Term
Placebo...
Subject Satisfaction Data: Overall Preference
Early Onset (15 Minutes) (N=6)
Product_Randomization * Preference Crosstabul...
Subject Satisfaction Data: Overall Preference
Early Onset (15 Minutes) (N=6)
System Organ Class
Preferred Term
Placebo
n=1...
Subject Satisfaction Data: Overall Preference
Early Onset (10 Minutes) (N=8)
Product_Randomization * Preference Crosstabul...
Subject Satisfaction Data: Overall Preference
Early Onset (10 Minutes) (N=8)
System Organ Class
Preferred Term
Placebo
n=1...
Subject Satisfaction Data: Overall Preference
Early Onset (5 Minutes) (N=6)
Product_Randomization * Preference Crosstabula...
Subject Satisfaction Data: Overall Preference
Early Onset (5 Minutes) (N=6)
System Organ Class
Preferred Term
Placebo
n=10...
Blinded Investigator’s Evaluation of Pain
Early Onset Groups Combined (N=20)
System Organ Class
Preferred Term
Placebo
n=1...
Blinded Investigator’s Overall Impression
Early Onset Groups Combined (N=20)
System Organ Class
Preferred Term
Placebo
n=1...
Blinded Investigator’s Evaluation of Pain
Early Onset (15 Minutes) (N=6)
Product_Randomization * Subject_Level_of_Pain Cro...
Blinded Investigator’s Evaluation of Pain
Early Onset (15 Minutes) (N=6)
System Organ Class
Preferred Term
Placebo
n=100
D...
Blinded Investigator’s Evaluation of Pain
Early Onset (10 Minutes) (N=8)
Product_Randomization * Subject_Level_of_Pain Cro...
Blinded Investigator’s Evaluation of Pain
Early Onset (10 Minutes) (N=8)
System Organ Class
Preferred Term
Placebo
n=100
D...
Blinded Investigator’s Evaluation of Pain
Early Onset (5 Minutes) (N=6)
Product_Randomization * Subject_Level_of_Pain Cros...
Blinded Investigator’s Evaluation of Pain
Early Onset (5 Minutes) (N=6)
System Organ Class
Preferred Term
Placebo
n=100
Dy...
Blinded Investigator’s Overall Impression
Early Onset Groups Combined (N=20)
Preferred Term, n (%) Placebo
n=100
Dysport 5...
Results: AE’s
 AE’s were all classified as minor and included
tenderness, bruising and edema all of which were
considered...
Results Summary I: Protocol 10025.1
 Subjective mean VAS scores for the 20 subjects
(combined early onset) indicated sign...
Results Summary II: Protocol 10025.1
 Subjective assessment for the 20 subjects (combined early onset) of
level of pain i...
Results Summary III: Protocol 10025.1
 Blinded investigators overall satisfaction (adequate
anesthesia) for the 20 subjec...
Results
Combined Trials
Efficacy Results: Subjective VAS
Overall Combined (N=50)
Group Statistics
50 1.806 1.3870 .1962
50 3.396 2.3788 .3364
50 ....
Efficacy Results: Subjective VAS
Overall Combined (N=50)
N=50 N=50 N=50
p<0.001 p=0.02 p=0.04
0
1
2
3
4
5
Immediate 1 Hour...
Subjective Level of Pain
Overall Combined (N=50)
Randomization * Subject_Level_of_Pain Crosstabulation
4 32 9 4 1 50
2.0 2...
Subjective Level of Pain
Overall Combined (N=50)
P<0.001
(B) LMX4(A) NTL4
Randomization
40
30
20
10
0
Count
Severe Pain
Mo...
Subject Satisfaction Data: Overall Preference
Overall Combined (N=50)
Product_Randomization * Preference Crosstabulation
3...
Subject Satisfaction Data: Overall
Preference Overall Combined (N=50)
System Organ Class
Preferred Term
Placebo
n=100
Dysp...
Blinded Investigator’s Evaluation of Pain
Overall Combined (N=50)
Randomization * Investigator_Rating Crosstabulation
19 2...
Blinded Investigator’s Evaluation of Pain
Overall Combined (N=50)
System Organ Class
Preferred Term
Placebo
n=100
Dysport ...
Blinded Investigator’s Overall Impression
Overall Combined (N=50)
System Organ Class
Preferred Term
Placebo
n=100
Dysport ...
Blinded Investigator’s Overall Impression
Overall Combined (N=50)
P<0.001
(B) LMX4(A) NTL4
Randomization
50
40
30
20
10
0
...
VAS Comparison: Onset
Immediate Post Injection
0
1
2
3
4
5
20 minutes 15 minutes 10 minutes 5 minutes
NTL4
LMX4
N=30 N=6 N...
VAS Comparison: Onset
One Hour Post Injection
N=30 N=6 N=8 N=6
p=0.016 p=0.085 p=0.279 p=0.309
d=1.1 (Large) d=0.56 (Mediu...
VAS Comparison: Onset
Three Hours Post Injection
N=30 N=6 N=8 N=6
p=0.066 p=0.22 p=0.724 p=0.643
d=0.48 (Medium) d=0.75 (L...
Results Summary Combined Trials
 All evaluations categories both subjective
and investigator assessed for combined
trials...
Discussion I
 Trails compared subjective and blinded investigator assessment pain,
as well as preference following Restyl...
Discussion II
 Significant effectiveness of NTL4 demonstrated in trials against
active compound (LMX4) not placebo
 AE’s...
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Lidocaine Comparison Trial Full

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Lidocaine Comparison Trial Full

  1. 1. NTL4 The Next Generation Topical Anesthetic Optimized Topical Lidocaine 4% 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.
  2. 2.  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 and confidential and protected under existing CDA  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. Disclosure
  3. 3.  The successful reduction of pain is one of the primary goals of medical care.  The medical management of pain encompasses pain related to injury, medical conditions and surgical procedures  The use of topical anesthetics (TA) is an important part of the management of pain both by physicians and consumers  In a recent study TA were prescribed or used 3.8 million times by physicians over a 5 year study interval and yet accounted for only a small fraction of the overall consumer use of TA  At the present time Dermatologists represent only a small fraction of physicians that use of TA, primarily using TA for minor surgical and cosmetic procedures Introduction Yentzer BA et al.: Utilization of Topical Anesthetics By Dermatologists in the US. Cosmetic Derm 22, 238 2009.
  4. 4.  TA are classified as RX, OTC or pharmacy compounded medications and contain a variety of ingredients from benzocaine to lidocaine to cocaine. Worldwide market estimated at over $5 billion in sales.  OTC Lidocaine (LMX4) is the most commonly used and prescribed TA by physicians  Important characteristics of TA include efficacy, onset and safety  The ideal TA would have the ability to provide a significant anesthetic effect shortly after application (5 – 10 minutes), have an excellent safety profile and be available to patients and physicians OTC  TA efficacy and onset limited by difficulty in drugs penetrating the skin barrier  Optimized drug delivery system can dramatically improve TA effectiveness, and onset and allow the use of safe, OTC strength compounds Topical Anesthetics Yentzer BA et al.: Utilization of Topical Anesthetics By Dermatologists in the US. Cosmetic Derm 22, 238 2009.
  5. 5. Topical Drug 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  The use of topical anesthetics is limited based on the difficulty that Lidocaine and other topical anesthetics to penetrate the skin  Ionic Nano Particle Technology (InParT) is a novel and unique delivery system that can be utilized to assist the transport topical anesthetics and of a variety of active compounds to target sites in the skin and beyond
  6. 6. 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
  7. 7. 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 particles size; less than 1-10 nano meters smaller than the skin pores  Nano Particles physically entraps active molecules without any changes in their chemical composition  Stabilizes the actives: shelf stable at room temperature for extended period of time without refrigeration  Uses all FDA approved ingredients
  8. 8. 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  The technology is easily scalable to any size
  9. 9. SEM-Photograph- 250x SEM-Photograph- 1000x
  10. 10.  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 sensory nerves  4% lidocaine is ideal because of it’s 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) on the contra lateral NLF as an active control  The initial trial investigated the efficacy and safety comparing a 20 minute application of both products  A second trial accessed early onset efficacy at 5, 10, and 15 minute application of both products NTL4
  11. 11. 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
  12. 12. Study Design: Protocol 10025  Two-center, randomized, split-face, double-blind pilot trial to evaluate the effectiveness of a test product NTL4 versus L-M-X4® 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.
  13. 13. Treatment  Topical NTL4 and LMX4 were randomly applied (20 second massage) to each NLF for 20 minutes and removed  Restylane was injected in the nasolabial fold area up to 1.5 ML per side on Injection Visit/ Visit 1.
  14. 14. Patient Assessments & Scale  Upon first needle stick of each of the NLF injections, the patient assessed the amount of pain associated with the procedure by completing a Visual Analog Scale (VAS) for the respective injection time:  Immediately after injection [1.0-10]  1 Hour after injection [1.0-10]  3 Hours after injection [1.0-10]  VAS: The patient drew a hash mark to indicate the degree of pain on a 10 cm line. The mark was measured in cm as a quantification of perceived pain: A separate evaluation will be performed for each side of the face at each time point. _____________________________________________________________________ No pain The worst pain you can imagine
  15. 15. Patient Assessments & Scale  1 Hour following injection, subjects were asked to complete a satisfaction survey addressing their assessment of the pain management options utilized.  Secondary endpoints obtained from this survey included:  Level of pain experienced on Left/Right Side when injected:  No Pain [0]  Slight Pain [1]  Moderate Pain [2]  Severe Pain [3]  Which topical anesthetic cream did you prefer?  Right [1]  Left [2]  No Preference [3]
  16. 16. Investigator Assessments  Upon injection, investigator completed a immediate assessment to evaluate severity of the patient’s pain using a 4-point scale  Upon injection, investigator completed a immediate assessment to evaluate the overall impression of the topical anesthetics (Investigator assessments were completed independent of patient assessment)  Facial photographs were obtained immediately following injection, 3 hours after injection and the next day.
  17. 17. Investigator Scale  The severity of the patient’s perceived pain during the procedure was scored on a 4-point grading system:  No Pain [0]  Slight Pain [1]  Moderate Pain [2]  Severe Pain [3]  The evaluation the overall impression of the topical anesthetics was scored using a 2-point system:  Did the Right/Left Side Topical provide adequate anesthesia for the dermal filler procedure?  Yes [1]  No [2]
  18. 18. Results
  19. 19. Efficacy Results: Subjective VAS Group Statistics 30 1.997 1.5736 .2873 30 3.087 2.4329 .4442 30 .217 .3086 .0563 30 .747 1.1227 .2050 30 .070 .1535 .0280 30 .313 .6942 .1267 Randomization (A) NTL4 (B) LMX4 (A) NTL4 (B) LMX4 (A) NTL4 (B) LMX4 VAS_Immediate VAS_1_Hour VAS_3_Hour N Mean Std. Deviation Std. Error Mean
  20. 20. Efficacy Results: Subjective VAS N=30 N=30 N=30 p=0.04 p=0.01 p=0.06 d=0.48 (Medium) X Axis: Time After Injection Y Axis: VAS Scale 0 1 2 3 4 5 Immediate 1 Hour 3 Hour NTL4 LMX4
  21. 21. Subject Satisfaction Data Subjective Level of Pain Randomization * Subject_Level_of_Pain Crosstabulation 2 18 7 2 1 30 1.0 15.0 9.0 3.5 1.5 30.0 6.7% 60.0% 23.3% 6.7% 3.3% 100.0% 100.0% 60.0% 38.9% 28.6% 33.3% 50.0% 3.3% 30.0% 11.7% 3.3% 1.7% 50.0% 0 12 11 5 2 30 1.0 15.0 9.0 3.5 1.5 30.0 .0% 40.0% 36.7% 16.7% 6.7% 100.0% .0% 40.0% 61.1% 71.4% 66.7% 50.0% .0% 20.0% 18.3% 8.3% 3.3% 50.0% 2 30 18 7 3 60 2.0 30.0 18.0 7.0 3.0 60.0 3.3% 50.0% 30.0% 11.7% 5.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 3.3% 50.0% 30.0% 11.7% 5.0% 100.0% Count Expected Count % within Randomization % within Subject_Level of_Pain % of Total Count Expected Count % within Randomization % within Subject_Level of_Pain % of Total Count Expected Count % within Randomization % within Subject_Level of_Pain % of Total (A) NTL4 (B) LMX4 Randomization Total No Pain Minimal Pain Mild Pain Moderate Pain Severe Pain Subject_Level_of_Pain Total
  22. 22. Subject Satisfaction Data Subjective Level of Pain P=0.22 (B) LMX4(A) NTL4 Randomization 20 15 10 5 0 Count Severe Pain Moderate Pain Mild Pain Minimal Pain No Pain Subject_Level_of_Pain Bar Chart
  23. 23. Subject Satisfaction Data Overall Preference Product_Randomization * Preference Crosstabulation 18 6 6 30 12.0 12.0 6.0 30.0 60.0% 20.0% 20.0% 100.0% 75.0% 25.0% 50.0% 50.0% 30.0% 10.0% 10.0% 50.0% 6 18 6 30 12.0 12.0 6.0 30.0 20.0% 60.0% 20.0% 100.0% 25.0% 75.0% 50.0% 50.0% 10.0% 30.0% 10.0% 50.0% 24 24 12 60 24.0 24.0 12.0 60.0 40.0% 40.0% 20.0% 100.0% 100.0% 100.0% 100.0% 100.0% 40.0% 40.0% 20.0% 100.0% Count Expected Count % within Product_ Randomization % within Preference % of Total Count Expected Count % within Product_ Randomization % within Preference % of Total Count Expected Count % within Product_ Randomization % within Preference % of Total NTL4 LMX Product_Randomization Total Yes No No Preference Preference Total
  24. 24. Subject Satisfaction Data Overall Preference System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients with any adverse event 43 (43) 104 (52) 147 (49) Eye disorders Eyelid edema 0 0 15 (8) 6 (3) 15 (5) 6 (2) General disorders and administrative site reactions Injection site pain Injection site hemorrhage 10 (10) 1 (1) 3 (3) 28 (14) 7 (4) 3 (2) 38 (13) 8 (3) 6 (2) Infections and Infestations Nasopharyngitis Upper respiratory tract infection 20 (20) 4 (4) 5 (5) 45 (23) 16 (8) 8 (4) 65 (22) 20 (7) 13 (4) Injury, poisoning, and procedural complications Postprocedural pain 8 (8) 3 (3) 10 (5) 2 (1) 18 (6) 5 (2) Investigations Blood urine present 2 (2) 1 (1) 8 (4) 6 (3) 10 (3) 7 (2) Nervous system disorders Headache 13 (13) 9 (9) 29 (15) 22 (11) 42 (14) 31 (10) 0 5 10 15 20 25 30 NTL4 LMX4 No Preference Subject Preference P=0.002 Preference Rates: NTL4 = 60% (18/30) LMX4 = 20% (6/30) No Preference = 20% (6/30)
  25. 25. Blinded Investigator’s Evaluation of Pain Randomization * Investigator_Rating Crosstabulation 11 17 2 0 30 6.0 17.5 5.0 1.5 30.0 36.7% 56.7% 6.7% .0% 100.0% 91.7% 48.6% 20.0% .0% 50.0% 18.3% 28.3% 3.3% .0% 50.0% 1 18 8 3 30 6.0 17.5 5.0 1.5 30.0 3.3% 60.0% 26.7% 10.0% 100.0% 8.3% 51.4% 80.0% 100.0% 50.0% 1.7% 30.0% 13.3% 5.0% 50.0% 12 35 10 3 60 12.0 35.0 10.0 3.0 60.0 20.0% 58.3% 16.7% 5.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 20.0% 58.3% 16.7% 5.0% 100.0% Count Expected Count % within Randomization % within Investigator_ Rating % of Total Count Expected Count % within Randomization % within Investigator_ Rating % of Total Count Expected Count % within Randomization % within Investigator_ Rating % of Total (A) NTL4 (B) LMX4 Randomization Total No Pain Slight Pain Moderate Pain Severe Pain Investigator_Rating Total
  26. 26. Blinded Investigator’s Evaluation of Pain System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients with any adverse event 43 (43) 104 (52) 147 (49) Eye disorders Eyelid edema 0 0 15 (8) 6 (3) 15 (5) 6 (2) General disorders and administrative site reactions Injection site pain Injection site hemorrhage 10 (10) 1 (1) 3 (3) 28 (14) 7 (4) 3 (2) 38 (13) 8 (3) 6 (2) Infections and Infestations Nasopharyngitis Upper respiratory tract infection 20 (20) 4 (4) 5 (5) 45 (23) 16 (8) 8 (4) 65 (22) 20 (7) 13 (4) Injury, poisoning, and procedural complications Postprocedural pain 8 (8) 3 (3) 10 (5) 2 (1) 18 (6) 5 (2) Investigations Blood urine present 2 (2) 1 (1) 8 (4) 6 (3) 10 (3) 7 (2) Nervous system disorders Headache 13 (13) 9 (9) 29 (15) 22 (11) 42 (14) 31 (10) P=0.002 (B) LMX4(A) NTL4 Randomization 20 15 10 5 0 Count Severe Pain Moderate Pain Slight Pain No Pain Investigator_Rating Bar Chart
  27. 27. Blinded Investigator’s Overall Satisfaction of Topical Anesthetic System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients reporting serious treatment-emergent adverse events: n (%) 1 (1) 4 (2) 5 (2) Cardiac disorders Cardiac flutter 0 1 (<1) 1 (<1) Gastrointestinal disorders Intestinal obstruction 1 (1) 0 1 (<1) General disorders and administrative site reactions Chest pain 0 1 (<1) 1 (<1) Infections and infestations Appendicitis 0 1 (<1) 1 (<1) Injury, poisoning, and procedural complications Burns second degree Burns third degree Thermal burn 1 (1) 1 (1) 1 (1) 0 0 0 1 (<1) 1 (<1) 1 (<1) Nervous system disorders Facial paresis 0 1 (<1) 1 (<1) Pregnancy, puerperium, and perinatal conditions Pregnancy 0 1 (<1) 1 (<1) Randomization * Overall_Impression_of_Anesthetic Crosstabulation 28 2 30 21.0 9.0 30.0 93.3% 6.7% 100.0% 66.7% 11.1% 50.0% 46.7% 3.3% 50.0% 14 16 30 21.0 9.0 30.0 46.7% 53.3% 100.0% 33.3% 88.9% 50.0% 23.3% 26.7% 50.0% 42 18 60 42.0 18.0 60.0 70.0% 30.0% 100.0% 100.0% 100.0% 100.0% 70.0% 30.0% 100.0% Count Expected Count % within Randomization % within Overall_ Impression_of_ Anesthetic % of Total Count Expected Count % within Randomization % within Overall_ Impression_of_ Anesthetic % of Total Count Expected Count % within Randomization % within Overall_ Impression_of_ Anesthetic % of Total (A) NTL4 (B) LMX4 Randomization Total Satisfied Not Satisfied Overall_Impression_of_ Anesthetic Total
  28. 28. Blinded Investigator’s Overall Satisfaction of Topical Anesthetic Preferred Term, n (%) Placebo n=100 Dysport 50 U n=200 Total N=300 Eyelid edema Probable Eyelid ptosis Probable Possible Asthenopia Probable Possible Vision blurred Possible Photopsia Probable 0 0 0 0 0 0 0 3 (2) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 3 (1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) P<0.001 (B) LMX4(A) NTL4 Randomization 30 25 20 15 10 5 0 Count Not Satisfied Satisfied Overall_Impression_of_Anesthetic Bar Chart
  29. 29. Results: AE’s  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
  30. 30. 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 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)
  31. 31. 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
  32. 32. 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
  33. 33. Study Design: Protocol 10025.1  Two-center, randomized, split-face, double-blind pilot trial to evaluate the onset and effectiveness of a test product NTL4 versus L-M-X4® 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  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.
  34. 34. Treatment  Topical NTL4 and LMX4 were randomly applied (30 second massage) to each NLF for 15, 10 or 5 minutes and removed  Restylane was injected in the nasolabial fold area up to 1.5 ML per side on Injection Visit/ Visit 1.
  35. 35. Patient Assessments & Scale  Upon first needle stick of each of the NLF injections, the patient assessed the amount of pain associated with the procedure by completing a Visual Analog Scale (VAS) for the respective injection time:  Immediately after injection [1.0-10]  1 Hour after injection [1.0-10]  3 Hours after injection [1.0-10]  VAS: The patient drew a hash mark to indicate the degree of pain on a 10 cm line. The mark was measured in cm as a quantification of perceived pain: A separate evaluation will be performed for each side of the face at each time point. _____________________________________________________________________ No pain The worst pain you can imagine
  36. 36. Patient Assessments & Scale  1 Hour following injection, subjects were asked to complete a satisfaction survey addressing their assessment of the pain management options utilized.  Secondary endpoints obtained from this survey included:  Level of pain experienced on Left/Right Side when injected:  No Pain [0]  Slight Pain [1]  Moderate Pain [2]  Severe Pain [3]  Which topical anesthetic cream did you prefer?  Right [1]  Left [2]  No Preference [3]
  37. 37. Investigator Assessments  Upon injection, investigator completed a immediate assessment to evaluate severity of the patient’s pain using a 4-point scale  Upon injection, investigator completed a immediate assessment to evaluate the overall impression of the topical anesthetics (Investigator assessments were completed independent of patient assessment)  Facial photographs were obtained immediately following injection, 3 hours after injection and the next day.
  38. 38. Investigator Scale  The severity of the patient’s perceived pain during the procedure was scored on a 4-point grading system:  No Pain [0]  Slight Pain [1]  Moderate Pain [2]  Severe Pain [3]  The evaluation the overall impression of the topical anesthetics was scored using a 2-point system:  Did the Right/Left Side Topical provide adequate anesthesia for the dermal filler procedure?  Yes [1]  No [2]
  39. 39. Results
  40. 40. Efficacy Results: Subjective VAS Early Onset Groups Combined (N=20) Group Statistics 20 1.520 1.0191 .2279 20 3.860 2.2763 .5090 20 .550 1.1963 .2675 20 1.120 1.7828 .3987 20 .380 .6978 .1560 20 1.025 1.8948 .4237 Product_Randomization NTL4 LMX4 NTL4 LMX4 NTL4 LMX4 VAS_Immediate VAS_1_Hour VAS_3_Hour N Mean Std. Deviation Std. Error Mean
  41. 41. Efficacy Results: Subjective VAS Early Onset Groups Combined (N=20) N=20 N=20 N=20 p<0.001 p=0.242 p=0.161 d=0.37 d=0.45 (Medium) X Axis: Time After Injection Y Axis: VAS Scale 0 1 2 3 4 5 Immediate 1 Hour 3 Hour NTL4 LMX4
  42. 42. Efficacy Results: Subjective VAS Early Onset (15 Minutes) (N=6) Group Statistics 6 1.917 1.1873 .4847 6 4.667 1.3721 .5602 6 .217 .2401 .0980 6 .983 .9517 .3885 6 .117 .2401 .0980 6 1.667 2.8884 1.1792 Product_Randomization NTL4 LMX4 NTL4 LMX4 NTL4 LMX4 VAS_Immediate VAS_1_Hour VAS_3_Hour N Mean Std. Deviation Std. Error Mean
  43. 43. Efficacy Results: Subjective VAS Early Onset (15 Minutes) (N=6) N=6 N=6 N=6 p<0.004 p=0.085 p=0.22 d=1.1 (Large) d=0.75 (Large) X Axis: Time After Injection Y Axis: VAS Scale 0 1 2 3 4 5 Immediate 1 Hour 3 Hour NTL4 LMX4
  44. 44. Efficacy Results: Subjective VAS Early Onset (10 Minutes) (N=8) Group Statistics 8 1.075 .8311 .2938 8 3.000 2.6306 .9301 8 .213 .4155 .1469 8 .863 1.5802 .5587 8 .525 .8137 .2877 8 .713 1.2287 .4344 Product_Randomization NTL4 LMX4 NTL4 LMX4 NTL4 LMX4 VAS_Immediate VAS_1_Hour VAS_3_Hour N Mean Std. Deviation Std. Error Mean
  45. 45. Efficacy Results: Subjective VAS Early Onset (10 Minutes) (N=8) N=8 N=8 N=8 p=0.068 p=0.279 p=0.724 d=0.98 (Large) d=0.56 (Medium) d=0.18 (Small) X Axis: Time After Injection Y Axis: VAS Scale 0 1 2 3 4 5 Immediate 1 Hour 3 Hour NTL4 LMX4
  46. 46. Efficacy Results: Subjective VAS Early Onset (5 Minutes) (N=6) Group Statistics 6 1.717 1.0088 .4118 6 4.200 2.4528 1.0013 6 .767 1.2533 .5116 6 2.167 2.9419 1.2010 6 .450 .8620 .3519 6 .800 1.5735 .6424 Product_Randomization NTL4 LMX4 NTL4 LMX4 NTL4 LMX4 VAS_Immediate VAS_1_Hour VAS_3_Hour N Mean Std. Deviation Std. Error Mean
  47. 47. Efficacy Results: Subjective VAS Early Onset (5 Minutes) (N=6) N=6 N=6 N=6 p=0.045 p=0.309 p=0.643 d=0.61 (Large) d=0.27 (Small) X Axis: Time After Injection Y Axis: VAS Scale 0 1 2 3 4 5 Immediate 1 Hour 3 Hour NTL4 LMX4
  48. 48. Subjective Level of Pain Early Onset Groups Combined (N=20) Product_Randomization * Subject_Level_of_Pain Crosstabulation 2 14 2 2 0 20 1.0 7.5 6.0 5.0 .5 20.0 10.0% 70.0% 10.0% 10.0% .0% 100.0% 100.0% 93.3% 16.7% 20.0% .0% 50.0% 5.0% 35.0% 5.0% 5.0% .0% 50.0% 0 1 10 8 1 20 1.0 7.5 6.0 5.0 .5 20.0 .0% 5.0% 50.0% 40.0% 5.0% 100.0% .0% 6.7% 83.3% 80.0% 100.0% 50.0% .0% 2.5% 25.0% 20.0% 2.5% 50.0% 2 15 12 10 1 40 2.0 15.0 12.0 10.0 1.0 40.0 5.0% 37.5% 30.0% 25.0% 2.5% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 5.0% 37.5% 30.0% 25.0% 2.5% 100.0% Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total NTL4 LMX4 Product_Randomization Total No Pain Minimal Pain Mild Pain Moderate Pain Severe Pain Subject_Level_of_Pain Total
  49. 49. Subjective Level of Pain Early Onset Groups Combined (N=20) P<0.001 LMX4NTL4 Product_Randomization 14 12 10 8 6 4 2 0 Count Severe Pain Moderate Pain Mild Pain Minimal Pain No Pain Subject_Level_of_Pain Bar Chart
  50. 50. Subjective Level of Pain Early Onset (15 Minutes) (N=6) Product_Randomization * Subject_Level_of_Pain Crosstabulation 5 0 1 6 2.5 1.0 2.5 6.0 83.3% .0% 16.7% 100.0% 100.0% .0% 20.0% 50.0% 41.7% .0% 8.3% 50.0% 0 2 4 6 2.5 1.0 2.5 6.0 .0% 33.3% 66.7% 100.0% .0% 100.0% 80.0% 50.0% .0% 16.7% 33.3% 50.0% 5 2 5 12 5.0 2.0 5.0 12.0 41.7% 16.7% 41.7% 100.0% 100.0% 100.0% 100.0% 100.0% 41.7% 16.7% 41.7% 100.0% Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total NTL4 LMX4 Product_Randomization Total Minimal Pain Mild Pain Moderate Pain Subject_Level_of_Pain Total
  51. 51. Subjective Level of Pain Early Onset (15 Minutes) (N=6) P=0.01 LMX4NTL4 Product_Randomization 5 4 3 2 1 0 Count Moderate Pain Mild Pain Minimal Pain Subject_Level_of_Pain Bar Chart
  52. 52. Subjective Level of Pain Early Onset (10 Minutes) (N=8) Product_Randomization * Subject_Level_of_Pain Crosstabulation 1 6 1 0 8 .5 3.0 4.0 .5 8.0 12.5% 75.0% 12.5% .0% 100.0% 100.0% 100.0% 12.5% .0% 50.0% 6.3% 37.5% 6.3% .0% 50.0% 0 0 7 1 8 .5 3.0 4.0 .5 8.0 .0% .0% 87.5% 12.5% 100.0% .0% .0% 87.5% 100.0% 50.0% .0% .0% 43.8% 6.3% 50.0% 1 6 8 1 16 1.0 6.0 8.0 1.0 16.0 6.3% 37.5% 50.0% 6.3% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 6.3% 37.5% 50.0% 6.3% 100.0% Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total NTL4 LMX4 Product_Randomization Total No Pain Minimal Pain Mild Pain Severe Pain Subject_Level_of_Pain Total
  53. 53. Subjective Level of Pain Early Onset (10 Minutes) (N=8) P=0.006 LMX4NTL4 Product_Randomization 7 6 5 4 3 2 1 0 Count Severe Pain Mild Pain Minimal Pain No Pain Subject_Level_of_Pain Bar Chart
  54. 54. Subjective Level of Pain Early Onset (5 Minutes) (N=6) System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients reporting serious treatment-emergent adverse events: n (%) 1 (1) 4 (2) 5 (2) Cardiac disorders Cardiac flutter 0 1 (<1) 1 (<1) Gastrointestinal disorders Intestinal obstruction 1 (1) 0 1 (<1) General disorders and administrative site reactions Chest pain 0 1 (<1) 1 (<1) Infections and infestations Appendicitis 0 1 (<1) 1 (<1) Injury, poisoning, and procedural complications Burns second degree Burns third degree Thermal burn 1 (1) 1 (1) 1 (1) 0 0 0 1 (<1) 1 (<1) 1 (<1) Nervous system disorders Facial paresis 0 1 (<1) 1 (<1) Pregnancy, puerperium, and perinatal conditions Pregnancy 0 1 (<1) 1 (<1) Product_Randomization * Subject_Level_of_Pain Crosstabulation 1 4 1 0 6 .5 2.5 1.0 2.0 6.0 16.7% 66.7% 16.7% .0% 100.0% 100.0% 80.0% 50.0% .0% 50.0% 8.3% 33.3% 8.3% .0% 50.0% 0 1 1 4 6 .5 2.5 1.0 2.0 6.0 .0% 16.7% 16.7% 66.7% 100.0% .0% 20.0% 50.0% 100.0% 50.0% .0% 8.3% 8.3% 33.3% 50.0% 1 5 2 4 12 1.0 5.0 2.0 4.0 12.0 8.3% 41.7% 16.7% 33.3% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 8.3% 41.7% 16.7% 33.3% 100.0% Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total NTL4 LMX4 Product_Randomization Total No Pain Minimal Pain Mild Pain Moderate Pain Subject_Level_of_Pain Total
  55. 55. Subjective Level of Pain Early Onset (5 Minutes) (N=6) Preferred Term, n (%) Placebo n=100 Dysport 50 U n=200 Total N=300 Eyelid edema Probable Eyelid ptosis Probable Possible Asthenopia Probable Possible Vision blurred Possible Photopsia Probable 0 0 0 0 0 0 0 3 (2) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 3 (1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) P=0.079 LMX4NTL4 Product_Randomization 4 3 2 1 0 Count Moderate Pain Mild Pain Minimal Pain No Pain Subject_Level_of_Pain Bar Chart
  56. 56. Subject Satisfaction Data: Overall Preference Early Onset Groups Combined (N=20) Product_Randomization * Preference Crosstabulation 17 3 20 10.0 10.0 20.0 85.0% 15.0% 100.0% 85.0% 15.0% 50.0% 42.5% 7.5% 50.0% 3 17 20 10.0 10.0 20.0 15.0% 85.0% 100.0% 15.0% 85.0% 50.0% 7.5% 42.5% 50.0% 20 20 40 20.0 20.0 40.0 50.0% 50.0% 100.0% 100.0% 100.0% 100.0% 50.0% 50.0% 100.0% Count Expected Count % within Product_ Randomization % within Preference % of Total Count Expected Count % within Product_ Randomization % within Preference % of Total Count Expected Count % within Product_ Randomization % within Preference % of Total NTL4 LMX Product_Randomization Total Yes No Preference Total
  57. 57. Subject Satisfaction Data: Overall Preference Early Onset Groups Combined (N=20) System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients with any adverse event 43 (43) 104 (52) 147 (49) Eye disorders Eyelid edema 0 0 15 (8) 6 (3) 15 (5) 6 (2) General disorders and administrative site reactions Injection site pain Injection site hemorrhage 10 (10) 1 (1) 3 (3) 28 (14) 7 (4) 3 (2) 38 (13) 8 (3) 6 (2) Infections and Infestations Nasopharyngitis Upper respiratory tract infection 20 (20) 4 (4) 5 (5) 45 (23) 16 (8) 8 (4) 65 (22) 20 (7) 13 (4) Injury, poisoning, and procedural complications Postprocedural pain 8 (8) 3 (3) 10 (5) 2 (1) 18 (6) 5 (2) Investigations Blood urine present 2 (2) 1 (1) 8 (4) 6 (3) 10 (3) 7 (2) Nervous system disorders Headache 13 (13) 9 (9) 29 (15) 22 (11) 42 (14) 31 (10) 0 5 10 15 20 NTL4 LMX4 No Preference Subject Preference P<0.001 Preference Rates: NTL4 = 85% (17/20) LMX4 = 15% (3/20) No Preference = 0% (0/20)
  58. 58. Subject Satisfaction Data: Overall Preference Early Onset (15 Minutes) (N=6) Product_Randomization * Preference Crosstabulation 6 0 6 3.0 3.0 6.0 100.0% .0% 100.0% 100.0% .0% 50.0% 50.0% .0% 50.0% 0 6 6 3.0 3.0 6.0 .0% 100.0% 100.0% .0% 100.0% 50.0% .0% 50.0% 50.0% 6 6 12 6.0 6.0 12.0 50.0% 50.0% 100.0% 100.0% 100.0% 100.0% 50.0% 50.0% 100.0% Count Expected Count % within Product_ Randomization % within Preference % of Total Count Expected Count % within Product_ Randomization % within Preference % of Total Count Expected Count % within Product_ Randomization % within Preference % of Total NTL4 LMX Product_Randomization Total Yes No Preference Total
  59. 59. Subject Satisfaction Data: Overall Preference Early Onset (15 Minutes) (N=6) System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients with any adverse event 43 (43) 104 (52) 147 (49) Eye disorders Eyelid edema 0 0 15 (8) 6 (3) 15 (5) 6 (2) General disorders and administrative site reactions Injection site pain Injection site hemorrhage 10 (10) 1 (1) 3 (3) 28 (14) 7 (4) 3 (2) 38 (13) 8 (3) 6 (2) Infections and Infestations Nasopharyngitis Upper respiratory tract infection 20 (20) 4 (4) 5 (5) 45 (23) 16 (8) 8 (4) 65 (22) 20 (7) 13 (4) Injury, poisoning, and procedural complications Postprocedural pain 8 (8) 3 (3) 10 (5) 2 (1) 18 (6) 5 (2) Investigations Blood urine present 2 (2) 1 (1) 8 (4) 6 (3) 10 (3) 7 (2) Nervous system disorders Headache 13 (13) 9 (9) 29 (15) 22 (11) 42 (14) 31 (10) 0 1 2 3 4 5 6 NTL4 LMX4 No Preference Subject Preference P=0.001 Preference Rates: NTL4 = 100% (6/6) LMX4 = 0% (0/6) No Preference = 0% (0/6)
  60. 60. Subject Satisfaction Data: Overall Preference Early Onset (10 Minutes) (N=8) Product_Randomization * Preference Crosstabulation 6 2 8 4.0 4.0 8.0 75.0% 25.0% 100.0% 75.0% 25.0% 50.0% 37.5% 12.5% 50.0% 2 6 8 4.0 4.0 8.0 25.0% 75.0% 100.0% 25.0% 75.0% 50.0% 12.5% 37.5% 50.0% 8 8 16 8.0 8.0 16.0 50.0% 50.0% 100.0% 100.0% 100.0% 100.0% 50.0% 50.0% 100.0% Count Expected Count % within Product_ Randomization % within Preference % of Total Count Expected Count % within Product_ Randomization % within Preference % of Total Count Expected Count % within Product_ Randomization % within Preference % of Total NTL4 LMX Product_Randomization Total Yes No Preference Total
  61. 61. Subject Satisfaction Data: Overall Preference Early Onset (10 Minutes) (N=8) System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients with any adverse event 43 (43) 104 (52) 147 (49) Eye disorders Eyelid edema 0 0 15 (8) 6 (3) 15 (5) 6 (2) General disorders and administrative site reactions Injection site pain Injection site hemorrhage 10 (10) 1 (1) 3 (3) 28 (14) 7 (4) 3 (2) 38 (13) 8 (3) 6 (2) Infections and Infestations Nasopharyngitis Upper respiratory tract infection 20 (20) 4 (4) 5 (5) 45 (23) 16 (8) 8 (4) 65 (22) 20 (7) 13 (4) Injury, poisoning, and procedural complications Postprocedural pain 8 (8) 3 (3) 10 (5) 2 (1) 18 (6) 5 (2) Investigations Blood urine present 2 (2) 1 (1) 8 (4) 6 (3) 10 (3) 7 (2) Nervous system disorders Headache 13 (13) 9 (9) 29 (15) 22 (11) 42 (14) 31 (10) 0 1 2 3 4 5 6 7 8 NTL4 LMX4 No Preference Subject Preference P=0.046 Preference Rates: NTL4 = 75% (6/8) LMX4 = 25% (2/8) No Preference = 0% (0/8)
  62. 62. Subject Satisfaction Data: Overall Preference Early Onset (5 Minutes) (N=6) Product_Randomization * Preference Crosstabulation 5 1 6 3.0 3.0 6.0 83.3% 16.7% 100.0% 83.3% 16.7% 50.0% 41.7% 8.3% 50.0% 1 5 6 3.0 3.0 6.0 16.7% 83.3% 100.0% 16.7% 83.3% 50.0% 8.3% 41.7% 50.0% 6 6 12 6.0 6.0 12.0 50.0% 50.0% 100.0% 100.0% 100.0% 100.0% 50.0% 50.0% 100.0% Count Expected Count % within Product_ Randomization % within Preference % of Total Count Expected Count % within Product_ Randomization % within Preference % of Total Count Expected Count % within Product_ Randomization % within Preference % of Total NTL4 LMX Product_Randomization Total Yes No Preference Total
  63. 63. Subject Satisfaction Data: Overall Preference Early Onset (5 Minutes) (N=6) System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients with any adverse event 43 (43) 104 (52) 147 (49) Eye disorders Eyelid edema 0 0 15 (8) 6 (3) 15 (5) 6 (2) General disorders and administrative site reactions Injection site pain Injection site hemorrhage 10 (10) 1 (1) 3 (3) 28 (14) 7 (4) 3 (2) 38 (13) 8 (3) 6 (2) Infections and Infestations Nasopharyngitis Upper respiratory tract infection 20 (20) 4 (4) 5 (5) 45 (23) 16 (8) 8 (4) 65 (22) 20 (7) 13 (4) Injury, poisoning, and procedural complications Postprocedural pain 8 (8) 3 (3) 10 (5) 2 (1) 18 (6) 5 (2) Investigations Blood urine present 2 (2) 1 (1) 8 (4) 6 (3) 10 (3) 7 (2) Nervous system disorders Headache 13 (13) 9 (9) 29 (15) 22 (11) 42 (14) 31 (10) 0 1 2 3 4 5 6 NTL4 LMX4 No Preference Subject Preference P=0.02 Preference Rates: NTL4 = 83% (5/6) LMX4 = 16% (1/6) No Preference = 0% (0/8)
  64. 64. Blinded Investigator’s Evaluation of Pain Early Onset Groups Combined (N=20) System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients with any adverse event 43 (43) 104 (52) 147 (49) Eye disorders Eyelid edema 0 0 15 (8) 6 (3) 15 (5) 6 (2) General disorders and administrative site reactions Injection site pain Injection site hemorrhage 10 (10) 1 (1) 3 (3) 28 (14) 7 (4) 3 (2) 38 (13) 8 (3) 6 (2) Infections and Infestations Nasopharyngitis Upper respiratory tract infection 20 (20) 4 (4) 5 (5) 45 (23) 16 (8) 8 (4) 65 (22) 20 (7) 13 (4) Injury, poisoning, and procedural complications Postprocedural pain 8 (8) 3 (3) 10 (5) 2 (1) 18 (6) 5 (2) Investigations Blood urine present 2 (2) 1 (1) 8 (4) 6 (3) 10 (3) 7 (2) Nervous system disorders Headache 13 (13) 9 (9) 29 (15) 22 (11) 42 (14) 31 (10) P<0.001 LMX4NTL4 Product_Randomization 12 10 8 6 4 2 0 Count Moderate Pain Mild Pain Minimal Pain No Pain Subject_Level_of_Pain Bar Chart
  65. 65. Blinded Investigator’s Overall Impression Early Onset Groups Combined (N=20) System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients reporting serious treatment-emergent adverse events: n (%) 1 (1) 4 (2) 5 (2) Cardiac disorders Cardiac flutter 0 1 (<1) 1 (<1) Gastrointestinal disorders Intestinal obstruction 1 (1) 0 1 (<1) General disorders and administrative site reactions Chest pain 0 1 (<1) 1 (<1) Infections and infestations Appendicitis 0 1 (<1) 1 (<1) Injury, poisoning, and procedural complications Burns second degree Burns third degree Thermal burn 1 (1) 1 (1) 1 (1) 0 0 0 1 (<1) 1 (<1) 1 (<1) Nervous system disorders Facial paresis 0 1 (<1) 1 (<1) Pregnancy, puerperium, and perinatal conditions Pregnancy 0 1 (<1) 1 (<1) Product_Randomization * Overall_Impression_of_Anesthetic Crosstabulation 20 0 20 15.0 5.0 20.0 100.0% .0% 100.0% 66.7% .0% 50.0% 50.0% .0% 50.0% 10 10 20 15.0 5.0 20.0 50.0% 50.0% 100.0% 33.3% 100.0% 50.0% 25.0% 25.0% 50.0% 30 10 40 30.0 10.0 40.0 75.0% 25.0% 100.0% 100.0% 100.0% 100.0% 75.0% 25.0% 100.0% Count Expected Count % within Product_ Randomization % within Overall_ Impression_of_ Anesthetic % of Total Count Expected Count % within Product_ Randomization % within Overall_ Impression_of_ Anesthetic % of Total Count Expected Count % within Product_ Randomization % within Overall_ Impression_of_ Anesthetic % of Total NTL4 LMX4 Product_Randomization Total Satisfied Not Satisfied Overall_Impression_of_ Anesthetic Total
  66. 66. Blinded Investigator’s Evaluation of Pain Early Onset (15 Minutes) (N=6) Product_Randomization * Subject_Level_of_Pain Crosstabulation 3 3 0 6 1.5 2.5 2.0 6.0 50.0% 50.0% .0% 100.0% 100.0% 60.0% .0% 50.0% 25.0% 25.0% .0% 50.0% 0 2 4 6 1.5 2.5 2.0 6.0 .0% 33.3% 66.7% 100.0% .0% 40.0% 100.0% 50.0% .0% 16.7% 33.3% 50.0% 3 5 4 12 3.0 5.0 4.0 12.0 25.0% 41.7% 33.3% 100.0% 100.0% 100.0% 100.0% 100.0% 25.0% 41.7% 33.3% 100.0% Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total NTL4 LMX4 Product_Randomization Total No Pain Minimal Pain Mild Pain Subject_Level_of_Pain Total
  67. 67. Blinded Investigator’s Evaluation of Pain Early Onset (15 Minutes) (N=6) System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients with any adverse event 43 (43) 104 (52) 147 (49) Eye disorders Eyelid edema 0 0 15 (8) 6 (3) 15 (5) 6 (2) General disorders and administrative site reactions Injection site pain Injection site hemorrhage 10 (10) 1 (1) 3 (3) 28 (14) 7 (4) 3 (2) 38 (13) 8 (3) 6 (2) Infections and Infestations Nasopharyngitis Upper respiratory tract infection 20 (20) 4 (4) 5 (5) 45 (23) 16 (8) 8 (4) 65 (22) 20 (7) 13 (4) Injury, poisoning, and procedural complications Postprocedural pain 8 (8) 3 (3) 10 (5) 2 (1) 18 (6) 5 (2) Investigations Blood urine present 2 (2) 1 (1) 8 (4) 6 (3) 10 (3) 7 (2) Nervous system disorders Headache 13 (13) 9 (9) 29 (15) 22 (11) 42 (14) 31 (10) P=0.02 LMX4NTL4 Product_Randomization 4 3 2 1 0 Count Mild Pain Minimal Pain No Pain Subject_Level_of_Pain Bar Chart
  68. 68. Blinded Investigator’s Evaluation of Pain Early Onset (10 Minutes) (N=8) Product_Randomization * Subject_Level_of_Pain Crosstabulation 3 5 0 0 8 1.5 5.0 1.0 .5 8.0 37.5% 62.5% .0% .0% 100.0% 100.0% 50.0% .0% .0% 50.0% 18.8% 31.3% .0% .0% 50.0% 0 5 2 1 8 1.5 5.0 1.0 .5 8.0 .0% 62.5% 25.0% 12.5% 100.0% .0% 50.0% 100.0% 100.0% 50.0% .0% 31.3% 12.5% 6.3% 50.0% 3 10 2 1 16 3.0 10.0 2.0 1.0 16.0 18.8% 62.5% 12.5% 6.3% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 18.8% 62.5% 12.5% 6.3% 100.0% Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total NTL4 LMX4 Product_Randomization Total No Pain Minimal Pain Mild Pain Moderate Pain Subject_Level_of_Pain Total
  69. 69. Blinded Investigator’s Evaluation of Pain Early Onset (10 Minutes) (N=8) System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients with any adverse event 43 (43) 104 (52) 147 (49) Eye disorders Eyelid edema 0 0 15 (8) 6 (3) 15 (5) 6 (2) General disorders and administrative site reactions Injection site pain Injection site hemorrhage 10 (10) 1 (1) 3 (3) 28 (14) 7 (4) 3 (2) 38 (13) 8 (3) 6 (2) Infections and Infestations Nasopharyngitis Upper respiratory tract infection 20 (20) 4 (4) 5 (5) 45 (23) 16 (8) 8 (4) 65 (22) 20 (7) 13 (4) Injury, poisoning, and procedural complications Postprocedural pain 8 (8) 3 (3) 10 (5) 2 (1) 18 (6) 5 (2) Investigations Blood urine present 2 (2) 1 (1) 8 (4) 6 (3) 10 (3) 7 (2) Nervous system disorders Headache 13 (13) 9 (9) 29 (15) 22 (11) 42 (14) 31 (10) P=0.112 LMX4NTL4 Product_Randomization 5 4 3 2 1 0 Count Moderate Pain Mild Pain Minimal Pain No Pain Subject_Level_of_Pain Bar Chart
  70. 70. Blinded Investigator’s Evaluation of Pain Early Onset (5 Minutes) (N=6) Product_Randomization * Subject_Level_of_Pain Crosstabulation 2 4 0 6 1.0 3.5 1.5 6.0 33.3% 66.7% .0% 100.0% 100.0% 57.1% .0% 50.0% 16.7% 33.3% .0% 50.0% 0 3 3 6 1.0 3.5 1.5 6.0 .0% 50.0% 50.0% 100.0% .0% 42.9% 100.0% 50.0% .0% 25.0% 25.0% 50.0% 2 7 3 12 2.0 7.0 3.0 12.0 16.7% 58.3% 25.0% 100.0% 100.0% 100.0% 100.0% 100.0% 16.7% 58.3% 25.0% 100.0% Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total Count Expected Count % within Product_ Randomization % within Subject_ Level_of_Pain % of Total NTL4 LMX4 Product_Randomization Total No Pain Minimal Pain Mild Pain Subject_Level_of_Pain Total
  71. 71. Blinded Investigator’s Evaluation of Pain Early Onset (5 Minutes) (N=6) System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients with any adverse event 43 (43) 104 (52) 147 (49) Eye disorders Eyelid edema 0 0 15 (8) 6 (3) 15 (5) 6 (2) General disorders and administrative site reactions Injection site pain Injection site hemorrhage 10 (10) 1 (1) 3 (3) 28 (14) 7 (4) 3 (2) 38 (13) 8 (3) 6 (2) Infections and Infestations Nasopharyngitis Upper respiratory tract infection 20 (20) 4 (4) 5 (5) 45 (23) 16 (8) 8 (4) 65 (22) 20 (7) 13 (4) Injury, poisoning, and procedural complications Postprocedural pain 8 (8) 3 (3) 10 (5) 2 (1) 18 (6) 5 (2) Investigations Blood urine present 2 (2) 1 (1) 8 (4) 6 (3) 10 (3) 7 (2) Nervous system disorders Headache 13 (13) 9 (9) 29 (15) 22 (11) 42 (14) 31 (10) P=0.076 LMX4NTL4 Product_Randomization 4 3 2 1 0 Count Mild Pain Minimal Pain No Pain Subject_Level_of_Pain Bar Chart
  72. 72. Blinded Investigator’s Overall Impression Early Onset Groups Combined (N=20) Preferred Term, n (%) Placebo n=100 Dysport 50 U n=200 Total N=300 Eyelid edema Probable Eyelid ptosis Probable Possible Asthenopia Probable Possible Vision blurred Possible Photopsia Probable 0 0 0 0 0 0 0 3 (2) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 3 (1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) P<0.001 LMX4NTL4 Product_Randomization 20 15 10 5 0 Count Not Satisfied Satisfied Overall_Impression_of_Anesthetic Bar Chart
  73. 73. Results: AE’s  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.
  74. 74. 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 were 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
  75. 75. 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 the10 minute and 5 minute incubations
  76. 76. 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.
  77. 77. Results Combined Trials
  78. 78. Efficacy Results: Subjective VAS Overall Combined (N=50) Group Statistics 50 1.806 1.3870 .1962 50 3.396 2.3788 .3364 50 .350 .7990 .1130 50 .896 1.4187 .2006 50 .194 .4757 .0673 50 .598 1.3422 .1898 Randomization (A) NTL4 (B) LMX4 (A) NTL4 (B) LMX4 (A) NTL4 (B) LMX4 VAS_Immediate VAS_1_Hour VAS_3_Hour N Mean Std. Deviation Std. Error Mean
  79. 79. Efficacy Results: Subjective VAS Overall Combined (N=50) N=50 N=50 N=50 p<0.001 p=0.02 p=0.04 0 1 2 3 4 5 Immediate 1 Hour 3 Hour NTL4 LMX4 X Axis: Time After Injection Y Axis: VAS Scale
  80. 80. Subjective Level of Pain Overall Combined (N=50) Randomization * Subject_Level_of_Pain Crosstabulation 4 32 9 4 1 50 2.0 22.5 15.0 8.5 2.0 50.0 8.0% 64.0% 18.0% 8.0% 2.0% 100.0% 100.0% 71.1% 30.0% 23.5% 25.0% 50.0% 4.0% 32.0% 9.0% 4.0% 1.0% 50.0% 0 13 21 13 3 50 2.0 22.5 15.0 8.5 2.0 50.0 .0% 26.0% 42.0% 26.0% 6.0% 100.0% .0% 28.9% 70.0% 76.5% 75.0% 50.0% .0% 13.0% 21.0% 13.0% 3.0% 50.0% 4 45 30 17 4 100 4.0 45.0 30.0 17.0 4.0 100.0 4.0% 45.0% 30.0% 17.0% 4.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 4.0% 45.0% 30.0% 17.0% 4.0% 100.0% Count Expected Count % within Randomization % within Subject_Level_ of_Pain % of Total Count Expected Count % within Randomization % within Subject_Level_ of_Pain % of Total Count Expected Count % within Randomization % within Subject_Level_ of_Pain % of Total (A) NTL4 (B) LMX4 Randomization Total No Pain Minimal Pain Mild Pain Moderate Pain Severe Pain Subject_Level_of_Pain Total
  81. 81. Subjective Level of Pain Overall Combined (N=50) P<0.001 (B) LMX4(A) NTL4 Randomization 40 30 20 10 0 Count Severe Pain Moderate Pain Mild Pain Minimal Pain No Pain Subject_Level_of_Pain Bar Chart
  82. 82. Subject Satisfaction Data: Overall Preference Overall Combined (N=50) Product_Randomization * Preference Crosstabulation 35 9 6 50 22.0 22.0 6.0 50.0 70.0% 18.0% 12.0% 100.0% 79.5% 20.5% 50.0% 50.0% 35.0% 9.0% 6.0% 50.0% 9 35 6 50 22.0 22.0 6.0 50.0 18.0% 70.0% 12.0% 100.0% 20.5% 79.5% 50.0% 50.0% 9.0% 35.0% 6.0% 50.0% 44 44 12 100 44.0 44.0 12.0 100.0 44.0% 44.0% 12.0% 100.0% 100.0% 100.0% 100.0% 100.0% 44.0% 44.0% 12.0% 100.0% Count Expected Count % within Product_ Randomization % within Preference % of Total Count Expected Count % within Product_ Randomization % within Preference % of Total Count Expected Count % within Product_ Randomization % within Preference % of Total NTL4 LMX Product_Randomization Total Yes No No Preference Preference Total
  83. 83. Subject Satisfaction Data: Overall Preference Overall Combined (N=50) System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients with any adverse event 43 (43) 104 (52) 147 (49) Eye disorders Eyelid edema 0 0 15 (8) 6 (3) 15 (5) 6 (2) General disorders and administrative site reactions Injection site pain Injection site hemorrhage 10 (10) 1 (1) 3 (3) 28 (14) 7 (4) 3 (2) 38 (13) 8 (3) 6 (2) Infections and Infestations Nasopharyngitis Upper respiratory tract infection 20 (20) 4 (4) 5 (5) 45 (23) 16 (8) 8 (4) 65 (22) 20 (7) 13 (4) Injury, poisoning, and procedural complications Postprocedural pain 8 (8) 3 (3) 10 (5) 2 (1) 18 (6) 5 (2) Investigations Blood urine present 2 (2) 1 (1) 8 (4) 6 (3) 10 (3) 7 (2) Nervous system disorders Headache 13 (13) 9 (9) 29 (15) 22 (11) 42 (14) 31 (10) 0 10 20 30 40 50 NTL4 LMX4 No Preference Subject Preference P<0.001 Preference Rates: NTL4 = 70% (35/50) LMX4 = 18% (9/50) No Preference = 12% (6/50)
  84. 84. Blinded Investigator’s Evaluation of Pain Overall Combined (N=50) Randomization * Investigator_Rating Crosstabulation 19 29 2 0 50 10.0 28.5 9.5 2.0 50.0 38.0% 58.0% 4.0% .0% 100.0% 95.0% 50.9% 10.5% .0% 50.0% 19.0% 29.0% 2.0% .0% 50.0% 1 28 17 4 50 10.0 28.5 9.5 2.0 50.0 2.0% 56.0% 34.0% 8.0% 100.0% 5.0% 49.1% 89.5% 100.0% 50.0% 1.0% 28.0% 17.0% 4.0% 50.0% 20 57 19 4 100 20.0 57.0 19.0 4.0 100.0 20.0% 57.0% 19.0% 4.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 20.0% 57.0% 19.0% 4.0% 100.0% Count Expected Count % within Randomization % within Investigator_ Rating % of Total Count Expected Count % within Randomization % within Investigator_ Rating % of Total Count Expected Count % within Randomization % within Investigator_ Rating % of Total (A) NTL4 (B) LMX4 Randomization Total No Pain Slight Pain Moderate Pain Severe Pain Investigator_Rating Total
  85. 85. Blinded Investigator’s Evaluation of Pain Overall Combined (N=50) System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients with any adverse event 43 (43) 104 (52) 147 (49) Eye disorders Eyelid edema 0 0 15 (8) 6 (3) 15 (5) 6 (2) General disorders and administrative site reactions Injection site pain Injection site hemorrhage 10 (10) 1 (1) 3 (3) 28 (14) 7 (4) 3 (2) 38 (13) 8 (3) 6 (2) Infections and Infestations Nasopharyngitis Upper respiratory tract infection 20 (20) 4 (4) 5 (5) 45 (23) 16 (8) 8 (4) 65 (22) 20 (7) 13 (4) Injury, poisoning, and procedural complications Postprocedural pain 8 (8) 3 (3) 10 (5) 2 (1) 18 (6) 5 (2) Investigations Blood urine present 2 (2) 1 (1) 8 (4) 6 (3) 10 (3) 7 (2) Nervous system disorders Headache 13 (13) 9 (9) 29 (15) 22 (11) 42 (14) 31 (10) P<0.001 (B) LMX4(A) NTL4 Randomization 30 25 20 15 10 5 0 Count Severe Pain Moderate Pain Slight Pain No Pain Investigator_Rating Bar Chart
  86. 86. Blinded Investigator’s Overall Impression Overall Combined (N=50) System Organ Class Preferred Term Placebo n=100 Dysport 50 U n=200 Total N=300 Patients reporting serious treatment-emergent adverse events: n (%) 1 (1) 4 (2) 5 (2) Cardiac disorders Cardiac flutter 0 1 (<1) 1 (<1) Gastrointestinal disorders Intestinal obstruction 1 (1) 0 1 (<1) General disorders and administrative site reactions Chest pain 0 1 (<1) 1 (<1) Infections and infestations Appendicitis 0 1 (<1) 1 (<1) Injury, poisoning, and procedural complications Burns second degree Burns third degree Thermal burn 1 (1) 1 (1) 1 (1) 0 0 0 1 (<1) 1 (<1) 1 (<1) Nervous system disorders Facial paresis 0 1 (<1) 1 (<1) Pregnancy, puerperium, and perinatal conditions Pregnancy 0 1 (<1) 1 (<1) Randomization * Overall_Impression_of_Anesthetic Crosstabulation 48 2 50 36.0 14.0 50.0 96.0% 4.0% 100.0% 66.7% 7.1% 50.0% 48.0% 2.0% 50.0% 24 26 50 36.0 14.0 50.0 48.0% 52.0% 100.0% 33.3% 92.9% 50.0% 24.0% 26.0% 50.0% 72 28 100 72.0 28.0 100.0 72.0% 28.0% 100.0% 100.0% 100.0% 100.0% 72.0% 28.0% 100.0% Count Expected Count % within Randomization % within Overall_ Impression_of_ Anesthetic % of Total Count Expected Count % within Randomization % within Overall_ Impression_of_ Anesthetic % of Total Count Expected Count % within Randomization % within Overall_ Impression_of_ Anesthetic % of Total (A) NTL4 (B) LMX4 Randomization Total Satisfied Not Satisfied Overall_Impression_of_ Anesthetic Total
  87. 87. Blinded Investigator’s Overall Impression Overall Combined (N=50) P<0.001 (B) LMX4(A) NTL4 Randomization 50 40 30 20 10 0 Count Not Satisfied Satisfied Overall_Impression_of_Anesthetic Bar Chart
  88. 88. VAS Comparison: Onset Immediate Post Injection 0 1 2 3 4 5 20 minutes 15 minutes 10 minutes 5 minutes NTL4 LMX4 N=30 N=6 N=8 N=6 p=0.044 p=0.004 p=0.068 p=0.045 d=0.98 (Large) X Axis: Duration of Application Y Axis: VAS Scale
  89. 89. VAS Comparison: Onset One Hour Post Injection N=30 N=6 N=8 N=6 p=0.016 p=0.085 p=0.279 p=0.309 d=1.1 (Large) d=0.56 (Medium) d=0.27 (Small) X Axis: Duration of Application Y Axis: VAS Scale 0 1 2 3 4 5 20 minutes 15 minutes 10 minutes 5 minutes NTL4 LMX4
  90. 90. VAS Comparison: Onset Three Hours Post Injection N=30 N=6 N=8 N=6 p=0.066 p=0.22 p=0.724 p=0.643 d=0.48 (Medium) d=0.75 (Large) d=0.18 (Small) d=0.27 (Small) 0 1 2 3 20 minutes 15 minutes 10 minutes 5 minutes NTL4 LMX4 X Axis: Duration of Application Y Axis: VAS Scale
  91. 91. Results Summary Combined Trials  All evaluations categories both subjective and investigator assessed for combined trials (n=50) demonstrated significantly less pain and significantly favored the NTL4 vs. LMX4 (p<0.01 or better)  VAS scores for NTL4 similar and independent of incubation time (20, 15, 10, 5 minutes) at immediate, one hour and three hours
  92. 92. 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)
  93. 93. Discussion II  Significant effectiveness of NTL4 demonstrated in trials against active compound (LMX4) not placebo  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 topical lidocaine 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)

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