1 11/8/00 Efficacy and Safety of Tacrolimus Ointment Ira D. Lawrence, M.D., F.A.C.P. Senior Vice President Research and Development Fujisawa Healthcare, Inc.

2 Five Core Phase III Studies Study12-Week, Double Blind Double Blind (12W, DB) 12-Month Open-Label (OL) AgeGroupPediatricAdultAdultPediatricAdult#Patients Study##37#35#36#25FG-12

3 Five Core Phase III Studies

4 12W, DB Studies - Adult (35/36) / Pediatric (37) Controlled Study Design BLW1W2W3W6W9W122W F/U Randomization Vehicle Ointment (twice daily) 0.03% Tacrolimus Ointment (twice daily) 0.1% Tacrolimus Ointment (twice daily)

5 12W, DB Studies - Adult (35/36) / Pediatric (37) Eligibility Criteria Atopic dermatitis: moderate to severe, > 10% BSA Atopic dermatitis: moderate to severe, > 10% BSA Concomitant therapy restrictions and washout requirements: 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

6 11/8/00 Results

7 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Patient Disposition Intent-to-Treat Completed Treatment Discontinued Lack of Efficacy Lack of Efficacy Adverse Event Adverse Event Administrative Administrative Reason Reason ‡ Vehicle32836%64%43%11%10% Concentration of Tacrolimus Ointment 0.03%32874%26% 9% 9% 6% 6%11%0.1%32779%21% 7% 7% 4% 4%10% Lost to follow-up, treatment noncompliance, patient refusal, etc. ‡ Lost to follow-up, treatment noncompliance, patient refusal, etc.

8 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Patient Demographics Gender:Female Male Race:Caucasian African American Other Age: Vehiclen=32855%45%66%26%8%22%13%65%Totaln=98355%45%66%27%7%22%14%64%0.03%n=32854%46%67%27%6%23%13%64%0.1%n=32757%43%65%27%7%21%15%64% Concentration of Tacrolimus Ointment No statistically significant differences among groups. 36%

9 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Baseline Disease Characteristics % BSA Affected > < 25 > < 50 > < 75 > < 100 Mean + SD Mean + SD Vehiclen=32829%30%20%21% Totaln=98330%29%21%20% %n=32833%28%21%18% %n=32728%30%22%20% Concentration of Tacrolimus Ointment 41%

10 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Baseline Disease Characteristics Severity Moderate Moderate Severe Severe With Head/Neck Involvement Vehiclen=32844%56%88%Totaln=98342%58%86%0.03%n=32842%58%86%0.1%n=32739%61%83% Concentration of Tacrolimus Ointment

11 Three, identically designed, 12 week, randomized, double-blind studies Three, identically designed, 12 week, randomized, double-blind studies Efficacy

12 12W, DB Studies - Adult (35/36) / Pediatric (37) Primary Efficacy Endpoint Physician’s Global Evaluation of Clinical Response at End of Treatment Physician’s Global Evaluation of Clinical Response at End of Treatment AssessmentCleared Excellent Improvement Marked Improvement Moderate Improvement Slight Improvement No Appreciable Improvement Worse % Improvement < 0

13 12W, DB Studies - Adult (35/36) / Pediatric (37) Analyses Performed for Success In each of the three pivotal studies, overall tests of equal proportions were performed 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. Since overall test (among three treatments) was significant in each of the three studies, each pairwise comparison was performed. First comparisons First comparisons 0.03% tacrolimus ointment vs. vehicle 0.1% tacrolimus ointment vs. vehicle Second comparison 0.1% vs. 0.03% tacrolimus ointment

14 12W, DB Studies - Adult (35/36) / Pediatric (37) Analyses Performed for Success Analyses were performed Analyses were performed – For each individual study – For data from the three studies combined Intent-to-treat population Intent-to-treat population Last observation carried forward Last observation carried forward

15 12W, DB Studies - Adult (35/36) / Pediatric (37) Success (>90% improvement) ***p < for either concentration of tacrolimus ointment compared with vehicle in all 3 studies. ointment compared with vehicle in all 3 studies. *** *** *** *** *** *** % Patients N = 351 N = 304 N = 328

16 % Patients Vehicle0.03%0.1% 7% 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Success (>90% improvement) *** N = 328 N = 327 N = 328 ***p < for either concentration of tacrolimus ointment compared with vehicle ointment compared with vehicle *** 30% 38%

17 12W, DB Studies - Adult (35/36) / Pediatric (37) > 50% Improvement ***p < for either concentration of tacrolimus ointment compared with vehicle % Patients Vehicle0.03%0.1% 22% 66% 75% *** *** Cleared/Excellent (> 90%)Marked/Moderate (> 50%)

18 12W, DB Studies - Adult (35/36) / Pediatric (37) > 50% Improvement at Week 1 and End of Treatment (EOT) % Patients wk1 EOT

19 Efficacy Confirmation: Secondary Endpoints Eczema Area and Severity Index (EASI) Eczema Area and Severity Index (EASI) Percent Body Surface Area (%BSA) affected Percent Body Surface Area (%BSA) affected Physician’s Assessment of Signs of Atopic Dermatitis Physician’s Assessment of Signs of Atopic Dermatitis Patient’s Assessment of Pruritus Patient’s Assessment of Pruritus

20 11/8/00 Comparison of 0.1% versus 0.03% Tacrolimus Ointment

21 12W, DB Studies - Adult (35/36) / Pediatric (37) Success (>90% improvement) 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% Concentration of Tacrolimus Ointment

22 12W, DB Studies - Adult (35/36) Success in Adults by Concentration by Baseline Disease Severity % Patients 38% 40% 19% 35%* * Significantly (p = 0.009) greater improvement - 0.1% vs 0.03%

23 12W, DB Studies - Adult (35/36) Success in Adults by Concentration by %BSA Affected at Baseline 10 - < 25% BSA >25 - < 50% BSA >50 - < 75% BSA >75 - < 100% BSA % Patients 45% 28% 34% 19% 31% 5% 30%* 48% * Significantly (p = 0.004) greater improvement - 0.1% vs 0.03%

24 12W, DB Studies - Adult (35/36) Success in Adults % Patients 27% 16% 29% 40%* * Significantly (p = 0.029) greater improvement - 0.1% vs 0.03%

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

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

27 Five Core Phase III Studies Study12-Week, Double Blind Double Blind (12W, DB) 12 Month, Open-Label Open-Label (OL) (OL)AgeGroupPediatricAdultAdultPediatricAdult #Patients Study# FG

28 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Median Treatment Days Median Days

29 Overall AE Application Site AE Non-applications Site AE Infections AE Resulting in Discontinuation Vehicle n=328 84% 60% 68% 54% 13% 0.03% n=328 90% 75% 70% 56% 7% ‡ Adjusted incidence rates based on Kaplan-Meier estimates at week % n=327 89% 72% 68% 58% 5% 0.03% vs vehicle < Treatment Group 0.1% vs vehicle p - value 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Adverse Events Adjusted Incidence Rates ‡

30 Active > Vehicle (significant) (not significant) Active < Vehicle (significant) Comparison of Active and Vehicle Using 95% Confidence Interval Observed Difference Confidence Interval No Apparent Difference

31 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Common Adverse Events (> 5%) ‡ Treatment Difference with 95% CI ‡ Adjusted incidence rates based on Kaplan-Meier estimates at week 12. Accidental Injury Allergic Reaction Skin Burning Skin Erythema Skin Infection Fever Flu- like Symptoms Headache Asthma Cough Increased Pharyngitis Pruritus % minus vehicle 0.1% minus vehicle

32 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Skin Burning Prevalence % Patients D4W1W2W6W9W12 W3

33 12W, DB Studies - Adult (35/36) / Pediatric (37) Adverse Events of Clinical Interest Adjusted Incidence Rates ‡ Overall Infections Flu-like Symptoms HeadacheFever Cough Increased PharyngitisVehicle(n=328)54%22%10% 8% 8% 7% 7% 6% 6%0.03%(n=328)56%25%14%10% 7% 7% 4% 4%0.1%(n=327)58%31%17% 7% 7% 6% 6% 5% 5% Concentration of Tacrolimus Ointment ‡ Adjusted incidence rates based on Kaplan-Meier estimates at week 12.

34 12W, DB Studies - Adult (35/36) / Pediatric (37) Cutaneous Events of Clinical Interest Adjusted Incidence Rates ‡ Skin Infection + Folliculitis Herpes Simplex Skin Tingling Alcohol Intolerance HyperesthesiaVehicle(n=328)12%<1% 3% 3% 2% 2% 0% 0%<1%0.03%(n=328)12% 5% 5% 4% 4% 3% 3% 2% 2% 0.1%(n=327)7%3%4%5%4%4% Concentration of Tacrolimus Ointment ‡ Adjusted incidence rates based on Kaplan-Meier estimates at week Majority presumed bacterial.

35 12W, DB Studies - Pediatric (37) Common Adverse Events in Children ‡ Treatment Difference with 95% CI ‡ Adjusted incidence rates based on Kaplan-Meier estimates at week 12. Skin Burning Skin Erythema Skin Infection Pharyngitis Pruritus Otitis Media Cough Increased Fever Flu-like Symptoms Headache % minus vehicle 0.1% minus vehicle

36 12W, DB Studies - Pediatric (37) Common Adverse Events in Children ‡ Treatment Difference with 95% CI ‡ Adjusted incidence rates based on Kaplan-Meier estimates at week 12. Sinusitis Pustular Rash Rhinitis Accidental Injury Allergic Reaction Asthma Abdominal Pain Infection Vomiting Bronchitis % minus vehicle 0.1% minus vehicle

37 12W, DB Studies - Pediatric (37) Adverse Event of Clinical Interest in Children Adjusted Incidence Rates ‡ Overall Infections Flu-like Symptoms Skin Infections Sinusitis Herpes Simplex Chicken Pox + Vehicle(n=116)48%25%14% 8% 8% 2% 2% 0% 0%0.03%(n=118)57%28%10% 3% 3% 2% 2% 5% 5%0.1%(n=118)55%32%11% 1% 1% 5% 5% 1% 1% Concentration of Tacrolimus Ointment + COSTART term Herpes Zoster. ‡ Adjusted incidence rates based on Kaplan-Meier estimates at week 12.

38 12W, DB Studies - Pediatric (37) Adverse Event Profile in Young Pediatric Patients -- Age 2-6 (n=215) Similar profile to overall pediatric patient population Similar profile to overall pediatric patient population No apparent difference in the 0.1% tacrolimus ointment and vehicle groups No apparent difference in the 0.1% tacrolimus ointment and vehicle groups Only statistically significant difference in 0.03% tacrolimus ointment group, versus vehicle Only statistically significant difference in 0.03% tacrolimus ointment group, versus vehicle – Pruritus – Chicken Pox (normal clinical course)

39 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. Accidental Injury Allergic Reaction Fever Flu-like Symptoms Headache Asthma Cough Increased Pharyngitis Pruritus Skin Burning Skin Erythema Skin Infection

40 12W, DB Studies - Adult (35/36) / Pediatric (37) Adverse Events Summary No apparent difference No apparent difference – Overall incidence adverse events – Overall non-application site events – Infections Higher incidence of local irritation events Higher incidence of local irritation events – Short duration – Occur early in treatment Both 0.03% and 0.1% concentrations are safe Both 0.03% and 0.1% concentrations are safe

41 Open-Label Studies Adult (FG-12) / Pediatric (25) Applied 0.1% tacrolimus ointment for 87% of days on study Applied 0.1% tacrolimus ointment for 87% of days on study Severe disease48% children 53% adults Severe disease48% children 53% adults Head/Neck80% children 95% adults Head/Neck80% children 95% adults > 6 months on study465 patients > 12 months on study248 patients > 6 months on study465 patients > 12 months on study248 patients

42 OL Studies - Adult (FG-12) / Pediatric (25) Summary of Raw Incidence of Adverse Events Number of Patients Overall Adverse Event AE Application Site AE Non-Application Site AE AE Resulting - D/C Pediatric n=255 87% 54% 77% 4% Adult n=316 92% 78% 75% 9%

43 OL Studies - Adult (FG-12) / Pediatric (25) Common (>10%) Application Site Events* Skin Burning Pruritus Skin Infection Skin Erythema Pediatric n=255 26% 23% 11% 9% Adult n=316 47% 24% 11% 12% * * > 5% incidence in both studies (also occurring at > 5% -10% incidence in FG-12: folliculitis, herpes simplex)

44 OL Studies - Adult (FG-12) / Pediatric (25) Common (>10%) Non-Application Site Adverse Events Flu-Like Symptoms Headache Fever Asthma Allergic Reaction Increased Cough Accidental Injury Infection Pediatric n=255 35% 18% 16% 15% 11% 8% Adult n=316 22% 10% 2% 5% 21% 3% 4% 14% Occurring > 5% to <10%: in 25, pharyngitis, sinusitus, bronchitis, diarrhea, vomiting, otitis media; in FG-12, pharyngitis, rhinitis, herpes simplex.

45 OL Studies - Adult (FG-12) / Pediatric (25) Non-Application Site Adverse Events No increase in non-application site adverse events with No increase in non-application site adverse events with – cumulative length of exposure – cumulative ointment use

46 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. 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.

47 Five Core Studies Hazard Rates 5 core studies 5 core studies 898 patients - 0.1% tacrolimus ointment 898 patients - 0.1% tacrolimus ointment Local irritation events excluded Local irritation events excluded All 898 patients included days All 898 patients included days Only long-term patients included > 90 days Only long-term patients included > 90 days

48 Five Core Studies Daily Hazard Rates + (SE) Over Time 0.1% Tacrolimus Ointment Flu-like Symptoms Headache Herpes Simplex FolliculitusLymphadenopathy Day (0.211) (0.163) (0.105) (0.091) (0.034) Day (0.169) (0.088) (0.079) (0.073) (0.047) Day (0.173) (0.069) (0.068) (0.047) (0.050) + Rate (SE) should be multiplied by 10 –3 to get actual rate.

49 OL Study – Pediatric (25) Lymphadenopathy Hazard Rates + (SE) Over Time 0.1% Tacrolimus Ointment - Pediatrics Hazard Rate (SE) (SE) Wks (0.0769) Wks (0.048) Wks (0.0737) + Rate (SE) should be multiplied by 10 –3 to get actual rate.

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

51 Lymphoma 2 cases of lymphoma reported in global development program 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

52 Five Core Studies Clinical Laboratory Evaluation No observed trends in laboratory profiles suggestive of safety concern No observed trends in laboratory profiles suggestive of safety concern

53 Safety Summary - Tacrolimus Ointment 0.03% & 0.1% Concentrations Adverse events do not increase with long term use (0.1% tacrolimus) Adverse events do not increase with long term use (0.1% tacrolimus) Adverse events are generally local irritation events (skin burning, pruritus) Adverse events are generally local irritation events (skin burning, pruritus) – Short duration – Occur early in treatment

54 Safety Summary - Tacrolimus Ointment 0.03% & 0.1% Concentrations Overall - no difference in tacrolimus vs. vehicle Overall - no difference in tacrolimus vs. vehicle – Non-application site events – Infection cluster (predefined) No trends in laboratory profile No trends in laboratory profile Adverse event profiles consistent between global and 5 core studies Adverse event profiles consistent between global and 5 core studies

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

56 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. 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.

57 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. 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.

58 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. 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.

59 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. 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.

60 Advisory Committee Questions Unrestriced Chronic Therapy vs. Time- Limited Acute Therapy AdultsChildren (> 2 years old) Unrestricted chronic intermittent therapy-patient should treat each episode of atopic dermatitis until clearing, plus seven days.

61 Advisory Committee Questions First-Line vs. Second- Line Treatment AdultsChildren (> 2 years old) First line therapy in adults and children 2 years of age and older.

62 Advisory Committee Questions 0.03%, 0.1%, Both, or Neither Adults 0.03% & 0.1% Children (> 2 years old) 0.03%

63 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. 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.

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

65 Tacrolimus Ointment 0.03%, 0.1% Novel, safe, and effective nonsteroidal topical therapy for the management of atopic dermatitis Novel, safe, and effective nonsteroidal topical therapy for the management of atopic dermatitis