Pulmonary-Allergy Drugs Advisory Committee

1
Topical Immunosuppressants (Calcineurin
Inhibitors) - Animal Toxicology
Barbara Hill, Ph.D. Division of Dermatologic and
Dental Drug Products
October 30, 2003
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Overall Objective

• Compare the animal toxicology data available for
  two topical immunosuppressants (Calcineurin
  Inhibitors) that have recently been approved for
  the topical treatment of atopic dermatitis
• Protopic (tacrolimus) ointment (12-8-00) and
  Elidel (pimecrolimus) cream (12-13-01)

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Outline

• Structures
• General Toxicology
• Genetic Toxicology Studies
• Photoco-carcinogenicity Studies
• Carcinogenicity Studies
• Overall Summary

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Structures

• Tacrolimus

• Pimecrolimus

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General Toxicology

• Potential immune target organs of toxicity
  identified in chronic rodent and nonrodent
  toxicology studies include thymus, lymph nodes
  and spleen
• Nonclinical toxicology study results indicate
  both compounds are classic immunosuppressive
  agents

6
Genetic Toxicology

• Tacrolimus
• Conducted an appropriate battery of in vitro and
  in vivo genotoxicity tests
• Non-genotoxic

• Pimecrolimus
• Conducted an appropriate battery of in vitro and
  in vivo genotoxicity tests
• Non-genotoxic

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Carcinogenic Mechanisms

• Not all carcinogens are direct acting genotoxic
  (DNA reactive) agents
• Indirect-acting carcinogens
• Do not interact directly with DNA
• Carcinogenesis is based on another mechanism
• e.g., hormones, immunosuppressants

8
Photoco-carcinogenicity Study

• Objective
• To determine in a hairless mouse model if dermal
  test article application combined with simulated
  sunlight exposure can reduce the time to
  formation of skin papillomas compared to
  simulated sunlight exposure alone

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Photoco-carcinogenicity Study

• A positive effect in this assay is referred to as
  an enhancement of the UV skin photo-carcinogenic
  effect, which is defined as shortening the time
  to skin tumor formation

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Photoco-carcinogenicity Study

• Tacrolimus
• Vehicle ointment enhanced UV photo-carcinogenesis
  
• Tacrolimus ointment had an additional small effect

• Pimecrolimus
• Vehicle cream enhanced UV photo-carcinogenesis
• Pimecrolimus cream had no additional effect

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Photoco-carcinogenicity Study

• Result of nonclinical finding
• a precaution was included in the label of each
  drug product advising patients to minimize or
  avoid exposure to natural or artificial sunlight
  while using the drug product

12
Carcinogenicity Studies

• Tacrolimus
• Oral rat
• Oral mouse
• Dermal mouse (marketed formulation)

• Pimecrolimus
• Oral rat
• Oral mouse
• Dermal rat (marketed formulation)
• Dermal mouse (ethanol - 13 week special high
  dose studies)

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Carcinogenicity Studies

• A treatment related tumor is identified as a
  statistically significant increase in the
  incidence of the tumor in treated animals
  compared to vehicle control animals
• Treatment related tumors are expressed in both
  labels as a multiple of human exposure based on
  AUC comparisons to the maximum recommended human
  dose (MRHD)

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Oral Carcinogenicity Studies - Lymphoma Signal
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Dermal Carcinogenicity Studies - Lymphoma Signal
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Carcinogenicity Studies - Other Tumor Signal
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Overall Summary

• Protopic (tacrolimus) ointment and Elidel
  (pimecrolimus) cream are topical
  immunosuppressants
• Neither tacrolimus or pimecrolimus exhibited a
  genotoxic signal
• Both Protopic ointment and Elidel cream contain
  cautionary wording in the labels to avoid
  sunlight exposure

18
Overall Summary

• A lymphoma signal was evident in a dermal mouse
  carcinogenicity study conducted with tacrolimus
  ointment
• A lymphoma signal was evident in an oral mouse
  carcinogenicity study conducted with pimecrolimus
• A lymphoma signal was evident in the 13 week
  dermal mouse study conducted with pimecrolimus
  dissolved in ethanol

19
Overall Summary

• The estimates of human systemic exposure data are
  highly variable and are dependent on the maximum
  body surface area that is treated in an atopic
  dermatitis patient
• Biologic plausibility of lymphoma formation in
  local lymph nodes can not be ruled out at this
  time (It is acknowledged that demonstrating this
  effect could be technically challenging)

20
Overall Summary

• Other tumor signals included
• Benign thymoma noted in the oral rat
  carcinogenicity study conducted with pimecrolimus
• Follicular cell adenoma of the thyroid noted in
  the dermal rat carcinogenicity study conducted
  with pimecrolimus cream

21
Overall Summary

• Based on the carcinogenic signals noted in
  nonclinical studies, registry studies were
  recommended as a phase 4 commitment for both
  Protopic (tacrolimus) ointment and Elidel
  (pimecrolimus) cream