A Novel Topical Transdermal Delivery System

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A Novel Topical Transdermal Delivery System

• Mark S. Nestor, M.D., Ph.D.
• Director
• Center for Clinical and Cosmetic Research
• Aventura Florida

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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

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InParT Drug Delivery SystemIonic 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

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InParT Drug Delivery SystemIonic 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

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InParT Drug Delivery SystemIonic 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)

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SEM-Photograph- 250x
SEM-Photograph- 1000x
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InParT Drug Delivery SystemClinical Investigation

• Topical Hyaluronic Acid
• Topical Lidocaine
• Acne
• Benzoyl Peroxide (BP)
• Topical Botulinum Neurotoxin Type A (BoNTA)
• Rhytids
• Hyperhidrosis
• Future Developments and Partnerships

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Topical Hyaluronic Acid (HA)
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InParT Drug Delivery SystemTopical 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

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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

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• 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

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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

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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

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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

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Trial Data
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Blinded Investigator Assessments
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Clinical Evaluation Skin Roughness
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Clinical Evaluation Skin Roughness
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Clinical Evaluation Skin Hydration
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Clinical Evaluation Skin Hydration
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Clinical Evaluation Skin Elasticity
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Clinical Evaluation Skin Elasticity
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Clinical Evaluation Skin Radiance
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Clinical Evaluation Skin Radiance
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Clinical Evaluation Smoothing Effect
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Clinical Evaluation Smoothing Effect
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Clinical Evaluation Overall Efficacy
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Clinical Evaluation Overall Efficacy
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Clinical Evaluation Tolerance
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Blinded Subjective Assessments
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Subjective Evaluation Wrinkle Improvement
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Subjective Evaluation Elasticity and Tightness
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Subjective Evaluation Elasticity and Tightness
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Subjective Evaluation Texture Improvement
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Subjective Evaluation Texture Improvement
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Subjective Evaluation Skin Hydration Improvement
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Subjective Evaluation Skin Hydration Improvement
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Subjective Evaluation Global Appearance
Improvement
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Subjective Evaluation Global Appearance
Improvement
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Subjective Evaluation Overall Efficacy
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Subjective Evaluation Overall Efficacy
CL1 Crosslinked HA (Restylane) NCL1 Non
Crosslinked HA Control Nano Technology
Vehicle
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Product Qualities
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Assessment of ProductSmell
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Assessment of ProductColor
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Assessment of ProductTexture
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Assessment of ProductEasiness of Application
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Assessment of ProductPenetration
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Assessment of ProductOverall Qualities of the
Cream
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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

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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

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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

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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

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90 Day Photos
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BEFORE
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BEFORE
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BEFORE
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BEFORE
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BEFORE
AFTER
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NTL4 The Next Generation Topical
AnestheticOptimized 4 Topical Lidocaine in a
Unique Nano Technology Delivery SystemResults
of Clinical Trials Comparing NTL4 to LMX4
Protocols N 1002510025.1
Center for Clinical and Cosmetic Research (CCCR),
Aventura, Florida Mark S. Nestor, M.D., Ph.D.
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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.

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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

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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

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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.
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Results Summary Protocol 10025

• Subjective mean VAS scores for the 30 subjects
  indicated significantly less pain upon injection
  (p0.04), one hour after injection (plt 0.01) and
  trend at 3 hours (p0.06) 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 (p0.002)
• Blinded investigator assessment of pain indicated
  significantly less pain on the NTL4 treated vs.
  LMX4 treated side (p0.002)
• Blinded investigators overall satisfaction
  (adequate anesthesia) significantly favored NTL4
  over LMX4 (plt 0.001)

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Results Summary Protocol 10025

• AEs 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 AEs for either NTL4 or LMX4

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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

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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.
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Results Summary I Protocol 10025.1

• Subjective mean VAS scores for the 20 subjects
  (combined early onset) indicated significantly
  less pain upon injection (plt0.001), 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 (p0.04) with trend favoring
  NTL4 at 10 minutes. Trends favoring NTL4 at one
  and three hours in all groups

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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
  (plt0.001). Individual onset groups significantly
  less pain favoring NTL4 over LMX4 for 15 minute
  and 5 minute incubations (p0.01, p0.006) with
  trend favoring NTL4 at 10 minutes.
• Subjects preference of topical anesthetic for the
  20 subjects (combined early onset) significantly
  favored NTL4 over LMX4 (p0.002). Individual
  onset groups significant preference favoring
  NTL4 over LMX4 for 15 minute 10 minute and 5
  minute incubations (p0.001, p 0.05, p0.02)
• Blinded investigator assessment of pain for the
  20 subjects (combined early onset) indicated
  significantly less pain on the NTL4 treated vs.
  LMX4 treated side (p0.001) Individual onset
  groups significantly less pain favoring NTL4
  over LMX4 for 15 minute (p0.02) with trends
  favoring NTL4 for the 10 minute and 5 minute
  incubations

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Results Summary III Protocol 10025.1

• Blinded investigators overall satisfaction
  (adequate anesthesia) for the 20 subjects
  (combined early onset) significantly favored NTL4
  over LMX4 (plt0.001). Individual onset groups
  significant preference favoring NTL4 over LMX4
  for 15 minute 10 minute and 5 minute incubations
  (p 0.05)
• AEs 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.

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Efficacy Results Subjective VAS Early Onset (5
Minutes) (N6)
X Axis Time After Injection Y Axis VAS Scale
N6 N6 N6
p0.045 p0.309
p0.643 d0.61 (Large) d0.27
(Small)
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Subjective Level of Pain Early Onset (5 Minutes)
(N6)
P0.079
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Subject Satisfaction Data Overall Preference
Early Onset (5 Minutes) (N6)
P0.02 Preference Rates NTL4 83
(5/6) LMX4 16 (1/6) No Preference 0 (0/8)
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Blinded Investigators Evaluation of PainEarly
Onset (5 Minutes) (N6)
P0.076
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VAS Comparison OnsetImmediate Post Injection
N30 N6 N8
N6 p0.044 p0.004
p0.068 p0.045
d0.98 (Large) X Axis Duration of Application Y
Axis VAS Scale
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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)

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Discussion II

• AEs 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)

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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

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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.

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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.

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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.

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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.

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Results
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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

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Results II
Table 1. VAS Scores N M SD Treated 10
1.1 .95 Non Treated 10 4.9 2.46
A one-way analysis of variance was used to test
mean differences between the 2 areas. Results
indicated that a significant difference exists
between the treated and non-treated areas (F
1,18 21.0, plt.001).
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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

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Topical BP CombinationAcne
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InParT Drug Delivery SystemTopical 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

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InParT Drug Delivery SystemTopical 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)

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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

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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).

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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.

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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.

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Topical BP Acne Pilot Clinical Study

• Results
• Overall disease severity score mean SD 3.71.7
• Mean percentage () change in papules and
  pustules
• Baseline week 1 week 2 week 4 week 6
  week 8
• 0 7.5 15.1 27.7
  40.1 56.3
• Incident of gt50 global improvement from baseline
  21/26
• Incident of gt75 global improvement from baseline
  14/26
• change non-inflammatory lesions counts 6422.2
• change inflammatory lesions counts
  6727.3

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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 3 weeks
6 weeks
113
Clinical Photographs
Baseline 3 weeks
6 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 SystemTopical 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 HyperhidrosisPilot Clinical Study
I

• Prospective open label study axillary and palmer
  hyperhidrosis
• 24 subjects (18 59)
• Starch Iodine and Gravimetric tests
• Botulinum toxin type A gel is applied, twice a
  day for 1 weeks, 6 units per day. (42 units at
  the end of the study).
• Weekly follow up for 12-16 weeks, with picture
  records, colorimetric and gravimetric test at
  week 4 and at the end of the study.
• Adverse effects were recorded.
• Patients answered a questionnaire of
  satisfaction at the end of the study.

Rogelio J, Morales O HYPERHIDROSIS TREATMENT
WITH TOPIC BOTULIN TOXIN TYPE A GEL Submitted .
120
Topical BoNTA HyperhidrosisPilot Clinical Study
II

• Analysis Friedman Test mg/min 79 reduction at
  12 weeks for all areas Plt0.0002
• Analysis Friedman Test cm2 89 reduction at 12
  weeks for all areas Plt0.004
• High Satisfaction Low AEs 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 (gt50 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
126
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128
Note Relative change from control similar in
Botox group
129
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130
Patient 1

• Baseline hyperhydrosis as defined by gravimetric
  test (gt50 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 1Baseline
Control Topical Dysport Gravimetric
Tests 129.0mg 102.9 mg
132
Patient 1Day 8
Control Topical Dysport Gravimetric
Tests 120.2 mg 13.7 mg
133
Patient 1Day 8
Control Topical Dysport Gravimetric
Tests 120.2 mg 13.7 mg
134
Patient 1Day 14
Control Topical Dysport Gravimetric
Tests 128.1 mg 14.0mg
135
Patient 1Day 14
Control Topical Dysport Gravimetric
Tests 128.1 mg 14.0 mg
136
Patient 1Day 30
Control Topical Dysport Gravimetric
Tests 100.9 mg 26.3mg
137
Patient 1Day 30
Control Topical Dysport Gravimetric
Tests 100.9 mg 26.3mg
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 SystemFuture Applications

• Hyperpigmentation and Melasma
• Psoriasis
• Rosacea
• Onychomycosis
• Xerosis
• Cosmeutical
• Hair Growth

140
InParT Drug Delivery SystemOpportunities

• Partnership vs. License Technology
• Enhance existing topical toxin
• HA
• Lidocaine
• Hydroquinone
• Collaborative effort
• Strategic Investment
• Sale