Efficacy and Safety of Tacrolimus Ointment Ira D. Lawrence, M.D., F.A.C.P. Senior Vice President Research and Development Fujisawa Healthcare, Inc.

1
Efficacy and Safetyof TacrolimusOintmentIra
D. Lawrence, M.D., F.A.C.P.Senior Vice
PresidentResearch and DevelopmentFujisawa
Healthcare, Inc.
2
Five Core Phase III Studies
Study 12-Week, Double Blind (12W,
DB) 12-Month Open-Label (OL)
Age Group Pediatric Adult Adult Pediatric Adult
Patients 351 304 328 255 316
Study 37 35 36 25 FG-12
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Five Core Phase III Studies
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12W, DB Studies - Adult (35/36) / Pediatric
(37)Controlled Study Design
0.03 Tacrolimus Ointment (twice daily)
0.1 Tacrolimus Ointment (twice daily)
Vehicle Ointment (twice daily)
Randomization
BL
W1
W2
W3
W6
W9
W12
2W F/U
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12W, DB Studies - Adult (35/36) / Pediatric
(37)Eligibility Criteria

• Atopic dermatitis moderate to severe, gt 10 BSA
• Concomitant therapy restrictions and washout
  requirements
• Emollients to treatment area
• Topical antihistamines and antimicrobials
• Topical or systemic corticosteroids
• Non-sedating systemic antihistamines
• Light treatments
• Non-steroidal immunosuppressants

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Results
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12W, DB Studies - Adult (35/36) / Pediatric (37)
CombinedPatient Disposition
Concentration of Tacrolimus Ointment
Vehicle 328 36 64 43 11 10
0.03 328 74 26 9 6 11
0.1 327 79 21 7 4 10
Intent-to-Treat Completed Treatment Disconti
nued Lack of Efficacy Adverse Event
Administrative Reason
Lost to follow-up, treatment noncompliance,
patient refusal, etc.
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12W, DB Studies - Adult (35/36) / Pediatric (37)
Combined Patient Demographics
Concentration of Tacrolimus Ointment
Vehicle n328 55 45 66 26 8 22 13 65
Total n983 55 45 66 27 7 22 14 64
0.03 n328 54 46 67 27 6 23 13 64
0.1 n327 57 43 65 27 7 21 15 64
Gender Female Male Race Caucasian African
American Other Age 2 - 6 7 - 15 16 -
79
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No statistically significant differences among
groups.
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12W, DB Studies - Adult (35/36) / Pediatric (37)
Combined Baseline Disease Characteristics
Concentration of Tacrolimus Ointment
Vehicle n328 29 30 20 21 47 27
Total n983 30 29 21 20 46 27
0.03 n328 33 28 21 18 45 27
0.1 n327 28 30 22 20 46 26
BSA Affected gt10 - lt 25 gt25 - lt 50
gt50 - lt 75 gt75 - lt 100 Mean SD
41
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12W, DB Studies - Adult (35/36) / Pediatric (37)
Combined Baseline Disease Characteristics
Concentration of Tacrolimus Ointment
Severity Moderate Severe With
Head/Neck Involvement
Vehicle n328 44 56 88
Total n983 42 58 86
0.03 n328 42 58 86
0.1 n327 39 61 83
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Efficacy

• Three, identically designed, 12 week, randomized,
  double-blind studies

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12W, DB Studies - Adult (35/36) / Pediatric
(37)Primary Efficacy Endpoint

• Physicians Global Evaluation ofClinical
  Response at End of Treatment

Assessment Cleared Excellent Improvement Marked
Improvement Moderate Improvement Slight
Improvement No Appreciable Improvement Worse
Improvement 100 90 - 99 75 - 89 50 - 74 30 -
49 0 - 29 lt 0
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12W, DB Studies - Adult (35/36) / Pediatric (37)
Analyses Performedfor Success

• In each of the three pivotal studies, overall
  tests of equal proportions were performed
• Since overall test (among three treatments) was
  significant in each of the three studies, each
  pairwise comparison was performed.
• First comparisons
• 0.03 tacrolimus ointment vs. vehicle
• 0.1 tacrolimus ointment vs. vehicle
• Second comparison
• 0.1 vs. 0.03 tacrolimus ointment

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12W, DB Studies - Adult (35/36) / Pediatric (37)
Analyses Performedfor Success

• Analyses were performed
• For each individual study
• For data from the three studies combined
• Intent-to-treat population
• Last observation carried forward

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12W, DB Studies - Adult (35/36) / Pediatric
(37)Success(gt90 improvement)
p lt 0.001 for either concentration of
tacrolimus ointment compared with vehicle in
all 3 studies.






Patients
N 351
N 304
N 328
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12W, DB Studies - Adult (35/36) / Pediatric
(37)Combined Success(gt90 improvement)
p lt 0.001 for either concentration of
tacrolimus ointment compared with vehicle

Patients
38

30
7
Vehicle
0.03
0.1
N 328
N 327
N 328
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12W, DB Studies - Adult (35/36) / Pediatric
(37)gt 50 Improvement
p lt 0.001 for either concentration of
tacrolimus ointment compared with vehicle

75

66
Patients
22
Vehicle
0.03
0.1
Cleared/Excellent (gt 90)
Marked/Moderate (gt 50)
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12W, DB Studies - Adult (35/36) / Pediatric
(37)gt 50 Improvement at Week 1 and End of
Treatment (EOT)
Patients
wk1
wk1
wk1
EOT
EOT
EOT
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Efficacy ConfirmationSecondary Endpoints

• Eczema Area and Severity Index (EASI)
• Percent Body Surface Area (BSA) affected
• Physicians Assessment of Signs of Atopic
  Dermatitis
• Patients Assessment of Pruritus

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Comparison of 0.1 versus 0.03 Tacrolimus
Ointment
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12W, DB Studies - Adult (35/36) / Pediatric
(37)Success(gt90 improvement)
Concentration of Tacrolimus Ointment
Pediatric (37) Adult (35) Adult (36) Adult
Studies Combined All Studies Combined
0.03 36 29 26 27 30
0.1 41 35 38 37 38
p-value 0.03 vs.0.1 0.401 0.369 0.060 0.041
0.038
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12W, DB Studies - Adult (35/36)Success in Adults
by Concentrationby Baseline Disease Severity
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38
35
Patients
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Significantly (p 0.009) greater improvement
- 0.1 vs 0.03
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12W, DB Studies - Adult (35/36)Success in Adults
by Concentration by BSA Affected at Baseline
48
45
34
31
30
28
Patients
19
5
10 - lt 25 BSA
gt25 - lt 50 BSA
gt50 - lt 75 BSA
gt75 - lt 100 BSA
Significantly (p 0.004) greater improvement
- 0.1 vs 0.03
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12W, DB Studies - Adult (35/36)Success in Adults
40
29
27
Patients
16
Significantly (p 0.029) greater improvement -
0.1 vs 0.03
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Efficacy Summary

• Both concentrations of tacrolimus ointment are
  effective
• Rapid improvement (1 week)
• In adults, 0.1 concentration more effective than
  0.03
• Effectiveness is maintained for periods up to 1
  year

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Safety Presentation

• Three 12 week, randomized, double-blind studies
• Each concentration versus vehicle
• Between two concentrations
• Two (up to 1 year) open-label safety studies
• Five core studies
• Hazard rates
• Laboratory profile data

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Five Core Phase III Studies
Study 12-Week, Double Blind (12W, DB) 12
Month, Open-Label (OL)
Age Group Pediatric Adult Adult Pediatric Adult

Patients 351 304 328 255 316
Study 37 35 36 25 FG-12
983
571
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12W, DB Studies - Adult (35/36) / Pediatric (37)
CombinedMedian Treatment Days
Median Days
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12W, DB Studies - Adult (35/36) / Pediatric (37)
CombinedAdverse EventsAdjusted Incidence Rates
Treatment Group
p - value
Overall AE Application Site
AE Non-applications Site AE Infections AE
Resulting in Discontinuation
Vehicle n328 84 60 68 54 13
0.03 n328 90 75 70 56 7
0.1 n327 89 72 68 58 5
0.03 vs vehicle 0.065 lt0.001 0.766
0.670 0.019
0.1 vs vehicle 0.158 0.001 0.880 0.522 0.002
Adjusted incidence rates based on Kaplan-Meier
estimates at week 12.
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Comparison of Active and VehicleUsing 95
Confidence Interval
-15
-10
-5
0
5
10
15
Active gt Vehicle (significant)
No Apparent Difference
(not significant)
Active lt Vehicle (significant)
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12W, DB Studies - Adult (35/36) / Pediatric (37)
CombinedCommon Adverse Events (gt 5)
Treatment Difference with 95 CI
35
25
15
5
-5
-15
Skin Burning
Pruritus
Flu- like Symptoms
Skin Erythema
Headache
Skin Infection
Fever
Allergic Reaction
Pharyngitis
Cough Increased
Asthma
Accidental Injury
Adjusted incidence rates based on Kaplan-Meier
estimates at week 12.
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12W, DB Studies - Adult (35/36) / Pediatric (37)
CombinedSkin Burning Prevalence
Patients
D4
W1
W2
W6
W9
W12
W3
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12W, DB Studies - Adult (35/36) / Pediatric
(37)Adverse Events of Clinical InterestAdjusted
Incidence Rates
Concentration of Tacrolimus Ointment
Overall Infections Flu-like
Symptoms Headache Fever Cough Increased Pharyngiti
s
Vehicle (n328) 54 22 10 8 7 6
0.03 (n328) 56 25 14 10 7 4
0.1 (n327) 58 31 17 7 6 5
Adjusted incidence rates based on Kaplan-Meier
estimates at week 12.
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12W, DB Studies - Adult (35/36) / Pediatric
(37)Cutaneous Events of Clinical
InterestAdjusted Incidence Rates
Concentration of Tacrolimus Ointment
Skin Infection Folliculitis Herpes
Simplex Skin Tingling Alcohol Intolerance Hyperest
hesia
Vehicle (n328) 12 lt1 3 2 0 lt1
0.03 (n328) 12 5 4 3 2 2
0.1 (n327) 7 3 4 5 4 4
Adjusted incidence rates based on Kaplan-Meier
estimates at week 12. Majority presumed
bacterial.
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12W, DB Studies - Pediatric (37)Common Adverse
Events in Children Treatment Difference with
95 CI
-20
-10
20
30
0
10
Skin Burning
Pruritus
Flu-like Symptoms
Fever
Cough Increased
Skin Erythema
Skin Infection
Headache
Otitis Media
Pharyngitis
Adjusted incidence rates based on Kaplan-Meier
estimates at week 12.
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12W, DB Studies - Pediatric (37)Common Adverse
Events in Children Treatment Difference with
95 CI
0
5
10
15
-20
-15
-10
-5
Asthma
Infection
Allergic Reaction
Sinusitis
Vomiting
Rhinitis
Pustular Rash
Abdominal Pain
Accidental Injury
Bronchitis
Adjusted incidence rates based on Kaplan-Meier
estimates at week 12.
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12W, DB Studies - Pediatric (37)Adverse Event of
Clinical Interest in ChildrenAdjusted Incidence
Rates
Concentration of Tacrolimus Ointment
Overall Infections Flu-like Symptoms Skin
Infections Sinusitis Herpes Simplex Chicken Pox
Vehicle (n116) 48 25 14 8 2 0
0.03 (n118) 57 28 10 3 2 5
0.1 (n118) 55 32 11 1 5 1
COSTART term Herpes Zoster.
Adjusted incidence rates based on Kaplan-Meier
estimates at week 12.
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12W, DB Studies - Pediatric (37)Adverse Event
Profile inYoung Pediatric Patients -- Age
2-6(n215)

• Similar profile to overall pediatric patient
  population
• No apparent difference in the 0.1 tacrolimus
  ointment and vehicle groups
• Only statistically significant difference in
  0.03 tacrolimus ointment group, versus vehicle
• Pruritus
• Chicken Pox (normal clinical course)

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12W, DB Studies - Adult (35/36) / Pediatric (37)
Combined 0.1 minus 0.03 with 95 CI Common
Adverse Events
Adjusted incidence rates based on Kaplan-Meier
estimates at week 12.
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12W, DB Studies - Adult (35/36) / Pediatric
(37)Adverse Events Summary

• No apparent difference
• Overall incidence adverse events
• Overall non-application site events
• Infections
• Higher incidence of local irritation events
• Short duration
• Occur early in treatment
• Both 0.03 and 0.1 concentrations are safe

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Open-Label StudiesAdult (FG-12) / Pediatric (25)

• Applied 0.1 tacrolimus ointment for 87 of days
  on study
• Severe disease 48 children 53 adults
• Head/Neck 80 children 95 adults
• gt 6 months on study 465 patientsgt 12 months on
  study 248 patients

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OL Studies - Adult (FG-12) / Pediatric
(25)Summary of Raw Incidence ofAdverse Events
Number of Patients Overall Adverse Event
AE Application Site AE Non-Application Site
AE AE Resulting - D/C
Pediatric n255 87 54 77 4
Adult n316 92 78 75 9
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OL Studies - Adult (FG-12) / Pediatric
(25)Common (gt10) ApplicationSite Events
Skin Burning Pruritus Skin Infection Skin
Erythema
Pediatric n255 26 23 11 9
Adult n316 47 24 11 12
gt 5 incidence in both studies (also occurring
at gt 5 -10 incidence in FG-12
folliculitis, herpes simplex)
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OL Studies - Adult (FG-12) / Pediatric
(25)Common (gt10) Non-ApplicationSite Adverse
Events
Flu-Like Symptoms Headache Fever Asthma Allergi
c Reaction Increased Cough Accidental
Injury Infection
Pediatric n255 35 18 18 16 15 15 11 8
Adult n316 22 10 2 5 21 3 4 14
Occurring gt 5 to lt10 in 25, pharyngitis,
sinusitus, bronchitis, diarrhea, vomiting, otitis
media in FG-12, pharyngitis, rhinitis, herpes
simplex.
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OL Studies - Adult (FG-12) / Pediatric
(25)Non-Application SiteAdverse Events

• No increase in non-application site adverse
  events with
• cumulative length of exposure
• cumulative ointment use

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Open-Label Safety Studies

• Tacrolimus 0.1 ointment is safe in the long-term
  treatment of atopic dermatitis when used for up
  to 1 year in children and adults.

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Five Core StudiesHazard Rates

• 5 core studies
• 898 patients - 0.1 tacrolimus ointment
• Local irritation events excluded
• All 898 patients included days 1- 89
• Only long-term patients included gt 90 days

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Five Core StudiesDaily Hazard Rates (SE) Over
Time0.1 Tacrolimus Ointment
Flu-like Symptoms Headache Herpes
Simplex Folliculitus Lymphadenopathy
Day 1-90 2.792 (0.211) 1.687 (0.163) 0.710
(0.105) 0.537 (0.091) 0.075 (0.034)
Day 91-182 0.986 (0.169) 0.292 (0.088) 0.248
(0.079) 0.219 (0.073) 0.093 (0.047)
Day 183-366 0.999 (0.173) 0.183 (0.069) 0.191
(0.068) 0.093 (0.047) 0.111 (0.050)
Rate (SE) should be multiplied by 10 3 to get
actual rate.
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OL Study Pediatric (25)Lymphadenopathy Hazard
Rates (SE)Over Time0.1 Tacrolimus Ointment -
Pediatrics
Hazard Rate (SE)
Wks 0-12 0.133 (0.0769)
Wks 12-26 0.048 (0.048)
Wks 26-52 0.147 (0.0737)
Rate (SE) should be multiplied by 10 3 to get
actual rate.
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COSTART CodeLymphadenopathy

• Most are secondary to concurrent inflammatory
  processes (tonsillitis, skin infections)
• Short-lived enlargements
• Shotty cervical lymph node
• Small cervical enlargement
• Common in atopic dermatitis
• Not associated with significant pathology

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Lymphoma

• 2 cases of lymphoma reported in global
  development program
• B Cell lymphoma in 68 year old patient,
  presenting in parotid (low grade follicular
  predated enrollment)
• CTCL in 60 year old patient with 7 year history
  of eczematous dermatitis

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Five Core StudiesClinical Laboratory Evaluation

• No observed trends in laboratory profiles
  suggestive of safety concern

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Safety Summary - Tacrolimus Ointment0.03 0.1
Concentrations

• Adverse events do not increase with long term use
  (0.1 tacrolimus)
• Adverse events are generally local irritation
  events (skin burning, pruritus)
• Short duration
• Occur early in treatment

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Safety Summary - Tacrolimus Ointment0.03 0.1
Concentrations

• Overall - no difference in tacrolimusvs. vehicle
• Non-application site events
• Infection cluster (predefined)
• No trends in laboratory profile
• Adverse event profiles consistent between global
  and 5 core studies

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Advisory Committee Questions

• Is Protopic 0.03 effective in the treatment of
  atopic dermatitis?Yes.In three 12-week double
  blindvehicle-controlled trials involving over
  300 patients in each study, 0.03 tacrolimus
  ointment was significantly superior to vehicle.

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Advisory Committee Questions

• Is Protopic 0.1 more effective than Protopic
  0.03 in adults? Yes.In two double-blind
  vehicle-controlled studies involving 632 adults,
  0.1 tacrolimus ointment was significantly more
  effective, particularily evident in patients with
  severe disease or extensive body surface area
  involvement.

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Advisory Committee Questions

• Is Protopic 0.1 more effective than Protopic
  0.03 in children?No.In our pediatric trials
  involving 351 children, there was no significant
  difference in efficacy between the two
  concentrations.

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Advisory Committee Questions

• Is Protopic safe for unrestricted chronic therapy
  as a first-line treatment in adults for both
  concentrations? Yes.The safety of the 0.1
  concentration of tacrolimus ointment in adults
  has been established for up to 1 year and thus,
  established safety in 0.03 tacrolimus ointment.

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Advisory Committee Questions

• Is Protopic safe for unrestricted chronic therapy
  as a first-line treatment in children for both
  concentrations?Yes.The safety of the 0.1
  concentration of tacrolimus ointment in children
  has been established for up to 1 year and thus,
  established safety in 0.03 tacrolimus ointment.

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Advisory Committee Questions
Unrestriced Chronic Therapy vs. Time-Limited
Acute Therapy
Unrestricted chronic intermittent therapy-patient
should treat each episode of atopic dermatitis
until clearing, plus seven days.
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Advisory Committee Questions
Adults
Children (gt 2 years old)
First-Line vs. Second-Line Treatment
First line therapy in adults and children 2 years
of age and older.
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Advisory Committee Questions
Adults 0.03 0.1
Children (gt 2 years old) 0.03
0.03, 0.1, Both, or Neither
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Advisory Committee Questions

• Are there additional studies needed for the
  labeling of Protopic and what are they?The NDA
  data summarized today clearly demonstrates the
  efficacy and safety of tacrolimus ointment and is
  sufficient to provide clear labeling for Protopic.

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Tacrolimus OintmentFurther Recommendations

• Patients should minimize or avoid unprotected
  exposure to natural or artificial sunlight during
  therapy
• Patients with unexplained fever or unexplained
  lymphadenopathy or suspected/proven infectious
  mononucleosis should delay or interrupt
  tacrolimus ointment therapy

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Tacrolimus Ointment0.03, 0.1

• Novel, safe, and effective nonsteroidal topical
  therapy for the management of atopic dermatitis