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A Novel Topical Transdermal Delivery System

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1 A Novel Topical Transdermal Delivery System
Mark S. Nestor, M.D., Ph.D. Director Center for Clinical and Cosmetic Research Aventura Florida

2 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

3 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

4 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

5 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)

6 SEM-Photograph- 250x SEM-Photograph- 1000x

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8 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

9 Topical Hyaluronic Acid (HA)

10 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

11 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

12 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

13 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 .

14 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 .

15 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 .

16 Trial Data

17 Blinded Investigator Assessments

18 Clinical Evaluation: Skin Roughness
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

19 Clinical Evaluation: Skin Roughness
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

20 Clinical Evaluation: Skin Hydration
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

21 Clinical Evaluation: Skin Hydration
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

22 Clinical Evaluation: Skin Elasticity
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

23 Clinical Evaluation: Skin Elasticity
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

24 Clinical Evaluation: Skin Radiance
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

25 Clinical Evaluation: Skin Radiance
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

26 Clinical Evaluation: Smoothing Effect
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

27 Clinical Evaluation: Smoothing Effect
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

28 Clinical Evaluation: Overall Efficacy
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

29 Clinical Evaluation: Overall Efficacy
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

30 Clinical Evaluation: Tolerance
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

31 Blinded Subjective Assessments

32 Subjective Evaluation: Wrinkle Improvement
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

33 Subjective Evaluation: Elasticity and Tightness
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

34 Subjective Evaluation: Elasticity and Tightness
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

35 Subjective Evaluation: Texture Improvement
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

36 Subjective Evaluation: Texture Improvement
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

37 Subjective Evaluation: Skin Hydration Improvement
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

38 Subjective Evaluation: Skin Hydration Improvement
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

39 Subjective Evaluation: Global Appearance Improvement
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

40 Subjective Evaluation: Global Appearance Improvement
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

41 Subjective Evaluation: Overall Efficacy
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

42 Subjective Evaluation: Overall Efficacy
CL1: Crosslinked HA (Restylane) NCL1: Non Crosslinked HA Control: Nano Technology Vehicle

43 Product Qualities

44 Assessment of Product Smell

45 Assessment of Product Color

46 Assessment of Product Texture

47 Assessment of Product Easiness of Application

48 Assessment of Product Penetration

49 Assessment of Product Overall Qualities of the Cream

50 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 .

51 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 .

52 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 .

53 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 .

54 90 Day Photos

55 49

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58 33 33 BEFORE

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68 BEFORE

69 BEFORE

70 BEFORE AFTER

71 Center for Clinical and Cosmetic Research (CCCR), Aventura, Florida
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° Center for Clinical and Cosmetic Research (CCCR), Aventura, Florida Mark S. Nestor, M.D., Ph.D.

72 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.

73 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

74 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

75 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.

76 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)

77 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

78 CCCR Protocol 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

79 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-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 (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.

80 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

81 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

82 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.

83 Efficacy Results: Subjective VAS Early Onset (5 Minutes) (N=6)
X Axis: Time After Injection Y Axis: VAS Scale N= N= N=6 p= p= p=0.643 d=0.61 (Large) d=0.27 (Small)

84 Subjective Level of Pain Early Onset (5 Minutes) (N=6)
LMX4 NTL4 Product_Randomization 4 3 2 1 Count Moderate Pain Mild Pain Minimal Pain No Pain Subject_Level_of_Pain Bar Chart P=0.079

85 Subject Satisfaction Data: Overall Preference Early Onset (5 Minutes) (N=6)
Preference Rates: NTL4 = 83% (5/6) LMX4 = 16% (1/6) No Preference = 0% (0/8)

86 Blinded Investigator’s Evaluation of Pain Early Onset (5 Minutes) (N=6)
LMX4 NTL4 Product_Randomization 4 3 2 1 Count Mild Pain Minimal Pain No Pain Subject_Level_of_Pain Bar Chart P=0.076

87 VAS Comparison: Onset Immediate Post Injection
N= N= N= N=6 p= p= p= p=0.045 d=0.98 (Large) X Axis: Duration of Application Y Axis: VAS Scale RLX 085-rev bh jb.ppt

88 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)

89 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)

90 Center for Clinical and Cosmetic Research
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

91 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.

92 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.

93 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.

94 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.

95 Results

96 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

97 Results II Table 1. VAS Scores N M SD Treated 10 1.1 .95
Non Treated 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).

98

99 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

100 Topical BP Combination Acne

101 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

102 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)

103 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

104 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).

105 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.

106 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.

107 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 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 ±27.3

108 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.

109

110 Clinical Photographs 4 weeks Baseline

111 Clinical Photographs Baseline 6 weeks

112 Clinical Photographs Baseline weeks weeks

113 Clinical Photographs Baseline weeks weeks

114 Topical Botulinum Neurotoxin
Hyperhidrosis

115 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  

116 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

117 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

118 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

119 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 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 .

120 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 .

121 Hyperhidrosis; Before and After ( at week 16)

122 Hyperhidrosis; Before and After ( at week 16)

123 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

124 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

125 Results

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128 Note: Relative change from control similar in Botox group

129

130 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

131 Patient 1 Baseline Control Topical Dysport Gravimetric Tests
129.0mg mg

132 Patient 1 Day 8 Control Topical Dysport Gravimetric Tests
120.2 mg mg

133 Patient 1 Day 8 Control Topical Dysport Gravimetric Tests
120.2 mg mg

134 Patient 1 Day 14 Control Topical Dysport Gravimetric Tests
128.1 mg mg

135 Patient 1 Day 14 Control Topical Dysport Gravimetric Tests
128.1 mg mg

136 Patient 1 Day 30 Control Topical Dysport Gravimetric Tests
100.9 mg mg

137 Patient 1 Day 30 Control Topical Dysport Gravimetric Tests
100.9 mg mg

138 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

139 InParT Drug Delivery System Future Applications
Hyperpigmentation and Melasma Psoriasis Rosacea Onychomycosis Xerosis Cosmeutical Hair Growth

140 InParT Drug Delivery System Opportunities
Partnership vs. License Technology Enhance existing topical toxin HA Lidocaine Hydroquinone Collaborative effort Strategic Investment Sale


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