Elidel

1
Elidel (pimecrolimus) Cream 1Safety Update
Feb, 2005

• Thomas Hultsch, MD
• Senior Medical Director
• Novartis Pharmaceuticals Corporation

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Overview

• No clinical evidence for increased risk of
  malignancies
• No evidence for systemic immunosuppression
• Pharmacokinetics
• Immunocompetence in children
• Infections rates in children
• Ongoing safety monitoring programs
• Conclusions

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Is there clinical evidence of increased risk of
malignancies?
CP-3
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ElidelThe Clinical Experience

• In clinical studies gt 19,000 patients since 1996
• 3,000 infants (3 - 24 mo)
• gt 7,000 children (2 - 17 yr)
• In clinical practice gt 5 million patients since
  Dec 2001
• 2.7 million patients lt 10 years of age
• Average Elidel usage
• Intermittently, 45 days/year
• 1.6 grams/day

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Reports of MalignanciesClinical Trials
Clinical trials (n 7)
Clinical studies show no evidence of an increased
risk of malignancies
Novartis data as of January 15, 2005.
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Reports of MalignanciesSpontaneous Reporting
Spontaneousreportsn 6
Lymphoma n 4
Skin tumors n 2
Male, 2.5 yr
Basal cell carcinoma male, 53 yr
Male, 53 yr
Squamouscell carcinoma female, 71 yr
Female, 61 yr
Unknown
Unconfirmed, poorly documented case,
non-US. Novartis data as of January 15, 2005.
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Non-Hodgkin LymphomasSpontaneous Reports
Treatment duration and regimen Extent of Elidel use
A few weeks, continuously 5 TBSA
6 months intermittent use 60 TBSA
6 monthsintermittent use 20 TBSA
Independentexpert assessmentof causality
Unlikely
Unlikely
Unlikely
Sex/age
Female61 yr
Male 53 yr
Male2.5 yr
Lymphoma histology(localization)
Histiocytic lymphoma (neck)
Subcutaneous panniculitis like T-cell lymphoma (trunk, limbs)
Lymphoblastic lymphoma (T cell)(mediastinum)
TBSA Total body surface area.
Novartis data as of January 15, 2005.
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No Evidence of Increased Incidence of NHL in Any
Age Group
lt 5 5 - 9 10 - 14 15 - 19 Totalchildren Adults Total(US)
Person-years of exposure 278,842 118,196 65,224 33,431 495,694 237,030 732,724
Expected no of cases (SEER), general population 1.8 1.0 0.7 0.5 4.0 42.1 46.1
SEER Surveillance, epidemiology, and end result.
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No Evidence of Immunosuppression

• Pharmacokinetics
• Objective measures of the immune response
• Vaccination responses (B-cell dependent)
• Delayed hypersensitivity (T-cell dependent)
• Infection rates

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PharmacokineticsTopical
Elidel Cream 1

• Pediatric PK studies, moderate to severe AD, up
  to 92 TBSA (75 pts/366 samples)
• 68 of samples lt 0.5 ng/mL
• 99 of samples lt 2.0 ng/mL
• 10 patients with measurable AUCs 11 - 38 ngh/mL

Skin surface
10,000 µg/g
700 µg/g
Stratum Corneum
Stratum Reticularis
30 µg/g
Basal cell layer
2 µg/g
Dermis
Blood circulation
0.0005 µg/g
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Toxicology StudyDermal
Highest exposure, topical, human pediatric
patients
38
Highest exposure, topical, human adult patients
23
0
200
400
600
800
1000
1200
AUC(0-24h) ng h/mL
No malignancies in mice exposed for 104 weeks at
27 the single highest AUC in pediatric patients
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Beyond Topical Application Oral Dosing in
Monkey Toxicology Study
27 highest human AUC
0
200
400
600
800
1000
1200
AUC(0-24h) ng h/mL
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Vaccination Response (B-cell Mediated)No Effect
of Elidel Treatment
Elidel
Range in general population according to
literature
82
Rubella
61 - 80
89
Measles
76 - 82
83
Diphtheria
79 - 92
91
Tetanus
92
92
0
20
40
60
80
100
Patients with protective antibody titre levels,
Papp K, et al. J Am Acad Dermatol.
200552247-253.
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Delayed Type Hypersensitivity (T-cell
Mediated)No Effect of Elidel Treatment
Children treated for 1 year (n 112)
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No Imbalance in Systemic Infections in Children
CS-15
Decreased
Increased
Bronchitis
Conjunctivitis
Ear infection
Enterobiasis
Gastroenteritis
Gastroenteritis viral
Influenza
Laryngitis
Lower respiratory tract infection
Nasopharyngitis
Otitis externa
Otitis media
Pharyngitis
Pharyngitis streptococcal
Pneumonia
Respiratory tract infection
Rhinitis
Sinusitis
Tonsillitis
Tooth abscess
Tracheitis
Upper respiratory tract infection
Urinary tract infection
Viral infection
Pyrexia
-4
-2
0
2
4
Log relative risk (Elidel/vehicle) with 95 CI
based on incidence density Elidel (n 1135),
vehicle (n 707)
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Skin Infections in Children
Decreased
Increased
Bacterial
Fungal
Parasitic
Skin infection non specified
Viral
-4
-2
0
2
4
Log relative risk (Elidel/vehicle) with 95 CI
based on incidence density Elidel (n 1135),
vehicle (n 707)
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Extensive Clinical Program Further Monitor
Elidel Safety

1. 6-year safety and efficacy study in infants 3 -
   18 mo, started Sep 2003 (n 1,100)
2. 5-year safety study in infants 3 - lt 12 mo,
   started Apr 2004 (n 2,400)
3. 10-year, prospective registry to assess risk of
   malignancies in children 2 - 17 yr, started Nov
   2004 (n 4,000)

• Controlled safety and efficacy study in
  HIV-positive patients
• Case control study to assess the risk of
  non-melanoma skin cancer in adults
• 6. Case control study to assess the risk of
  melanoma skin cancer in adults

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Elidel CreamConclusion

• Clinical data do not show evidence for an
  increased risk of malignancies
• Systemic immunosuppression is clinically
  implausible based on
• Pharmacokinetics (minimal blood levels)
• Maintained immunocompetence
• No increased risk of systemic infections

• Extensive clinical program further monitor Elidel
  safety