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

Efficacy and Safety of Tacrolimus Ointment Ira D. Lawrence, M.D., F.A.C.P. Senior Vice President Research and Development Fujisawa Healthcare, Inc. Five Core Phase III Studies. Study 12-Week, Double Blind (12W, DB) 12-Month Open-Label (OL). Age Group Pediatric Adult Adult

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

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  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 Study # #37 #35 #36 #25 FG-12 # Patients 351 304 328 255 316

  3. Five Core Phase III Studies

  4. 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

  5. 12W, DB Studies - Adult (35/36) / Pediatric (37)Eligibility Criteria • Atopic dermatitis: moderate to severe, > 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

  6. Results

  7. 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 Discontinued Lack of Efficacy Adverse Event Administrative Reason ‡ ‡Lost to follow-up, treatment noncompliance, patient refusal, etc.

  8. 12W, DB Studies - Adult (35/36) / Pediatric (37) CombinedPatient Demographics Concentration of Tacrolimus Ointment Vehicle n=328 55% 45% 66% 26% 8% 22% 13% 65% 0.03% n=328 54% 46% 67% 27% 6% 23% 13% 64% 0.1% n=327 57% 43% 65% 27% 7% 21% 15% 64% Total n=983 55% 45% 66% 27% 7% 22% 14% 64% Gender: Female Male Race: Caucasian African American Other Age: 2 - 6 7 - 15 16 - 79 36% No statistically significant differences among groups.

  9. 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Baseline Disease Characteristics Concentration of Tacrolimus Ointment Vehicle n=328 29% 30% 20% 21% 47 + 27 0.03% n=328 33% 28% 21% 18% 45 + 27 0.1% n=327 28% 30% 22% 20% 46 + 26 Total n=983 30% 29% 21% 20% 46 + 27 % BSA Affected >10 - < 25 >25 - < 50 >50 - < 75 >75 - < 100 Mean + SD 41%

  10. 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined Baseline Disease Characteristics Concentration of Tacrolimus Ointment Severity Moderate Severe With Head/Neck Involvement Vehicle n=328 44% 56% 88% 0.03% n=328 42% 58% 86% 0.1% n=327 39% 61% 83% Total n=983 42% 58% 86%

  11. 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 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 < 0

  13. 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

  14. 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

  15. 12W, DB Studies - Adult (35/36) / Pediatric (37)Success(>90% improvement) ***p < 0.001 for either concentration of tacrolimus ointment compared with vehicle in all 3 studies. *** *** *** *** *** *** % Patients N = 351 N = 304 N = 328

  16. 12W, DB Studies - Adult (35/36) / Pediatric (37)Combined Success(>90% improvement) ***p < 0.001 for either concentration of tacrolimus ointment compared with vehicle *** % Patients 38% *** 30% 7% Vehicle 0.03% 0.1% N = 328 N = 328 N = 327

  17. 12W, DB Studies - Adult (35/36) / Pediatric (37)>50% Improvement ***p < 0.001 for either concentration of tacrolimus ointment compared with vehicle *** 75% *** 66% % Patients 22% Vehicle 0.03% 0.1% 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 wk1 EOT wk1 EOT

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

  20. Comparison of 0.1% versus 0.03% Tacrolimus Ointment

  21. 12W, DB Studies - Adult (35/36) / Pediatric (37)Success(>90% 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

  22. 12W, DB Studies - Adult (35/36)Success in Adults by Concentrationby Baseline Disease Severity 40% 38% 35%* % Patients 19% * 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 48% 45% 34% 31% 30%* 28% % Patients 19% 5% 10 - < 25% BSA >25 - < 50% BSA >50 - < 75% BSA >75 - < 100% BSA * Significantly (p = 0.004) greater improvement - 0.1% vs 0.03%

  24. 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%

  25. 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

  26. 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 Safety Presentation

  27. 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

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

  29. 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 n=328 84% 60% 68% 54% 13% 0.03% n=328 90% 75% 70% 56% 7% 0.1% n=327 89% 72% 68% 58% 5% 0.03% vs vehicle 0.065 <0.001 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.

  30. Observed Difference Confidence Interval Comparison of Active and VehicleUsing 95% Confidence Interval 0 -10 5 10 -15 -5 15 Active > Vehicle (significant) No Apparent Difference (not significant) Active < Vehicle (significant)

  31. 0.03% minus vehicle 0.1% minus vehicle 12W, DB Studies - Adult (35/36) / Pediatric (37) CombinedCommon Adverse Events (> 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.

  32. 12W, DB Studies - Adult (35/36) / Pediatric (37) CombinedSkin Burning Prevalence % Patients D4 W1 W2 W6 W9 W12 W3

  33. 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 Pharyngitis Vehicle (n=328) 54% 22% 10% 8% 7% 6% 0.03% (n=328) 56% 25% 14% 10% 7% 4% 0.1% (n=327) 58% 31% 17% 7% 6% 5% ‡Adjusted incidence rates based on Kaplan-Meier estimates at week 12.

  34. 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 Hyperesthesia Vehicle (n=328) 12% <1% 3% 2% 0% <1% 0.03% (n=328) 12% 5% 4% 3% 2% 2% 0.1% (n=327) 7% 3% 4% 5% 4% 4% ‡Adjusted incidence rates based on Kaplan-Meier estimates at week 12. + Majority presumed bacterial.

  35. 0.03% minus vehicle 0.1% minus vehicle 12W, DB Studies - Pediatric (37)Common Adverse Events in Children‡Treatment Difference with 95% CI -20 20 30 -10 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.

  36. 0.03% minus vehicle 0.1% minus vehicle 12W, DB Studies - Pediatric (37)Common Adverse Events in Children‡Treatment Difference with 95% CI 15 10 0 5 -15 -10 -5 -20 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.

  37. 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 (n=116) 48% 25% 14% 8% 2% 0% 0.03% (n=118) 57% 28% 10% 3% 2% 5% 0.1% (n=118) 55% 32% 11% 1% 5% 1% + COSTART term Herpes Zoster. ‡Adjusted incidence rates based on Kaplan-Meier estimates at week 12.

  38. 12W, DB Studies - Pediatric (37)Adverse Event Profile inYoung Pediatric Patients -- Age 2-6(n=215) • 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)

  39. -10 10 -20 20 0 Skin Burning Pruritus Flu-like Symptoms Skin Erythema Headache Skin Infection Fever Allergic Reaction Pharyngitis Cough Increased Asthma Accidental Injury 12W, DB Studies - Adult (35/36) / Pediatric (37) Combined0.1% minus 0.03% with 95% CICommon Adverse Events‡ ‡Adjusted incidence rates based on Kaplan-Meier estimates at week 12.

  40. 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

  41. 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 • > 6 months on study 465 patients> 12 months on study 248 patients

  42. 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 n=255 87% 54% 77% 4% Adult n=316 92% 78% 75% 9%

  43. OL Studies - Adult (FG-12) / Pediatric (25)Common (>10%) ApplicationSite 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-ApplicationSite Adverse Events Flu-Like Symptoms Headache Fever Asthma Allergic Reaction Increased Cough Accidental Injury Infection Pediatric n=255 35% 18% 18% 16% 15% 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 SiteAdverse Events • 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.

  47. 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 > 90 days

  48. 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.

  49. 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.

  50. COSTART Code“Lymphadenopathy” • 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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