James G. Farrelly, Ph.D. Pharmacology Team Leader

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James G. Farrelly, Ph.D.Pharmacology Team Leader

• Division of Antiviral Drug Products
• Center for Drug Evaluation and Research
• Food and Drug Administration

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Entecavir Genetic Toxicity

• Entecavir is a nucleoside analog, a member of a
  class of molecules expected to be genetically
  toxic
• Mode of action is consistent with its being a
  mutagen or a clastogen
• Not an obligate chain terminator
• It halts DNA synthesis after the addition of a
  few bases into the growing chain
• It is clastogenic in vitro in a human lymphocyte
  assay
• It is negative in the Ames assay and in a number
  of in vitro and in vivo genetic toxicology
  assays.
• It is negative in the SHE-cell transformation
  assay

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Genetic toxicity

• Adefovir
• Mutagenic in vitro
• Induced chromosomal aberrations in vitro
• Lamivudine
• Mutagenic in two in vitro assays
• Interferon
• Not a genetic toxin

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Male Rat Tumor Data
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Female Rat Tumor Data
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Male Mouse Tumor Data
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Female Mouse Tumor Data
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Carcinogenicity Studies

• Interferon
• No carcinogenicity studies carried out
• Adefovir
• Negative for carcinogenicity
• Exposures in studies 10-fold for mice and 4-fold
  for rats
• Lamivudine
• Negative for carcinogenicity
• Exposure in studies 34-fold in mice and 200-fold
  in rats

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Carcinogenicity Assessment Committee

• CAC founded in the late 1980s
• Founded to examine carcinogenicity protocols
• Also interprets the outcome of carcinogenicity
  studies
• Ensures that the assessment of protocols and
  studies will be consistent among review divisions
• Two committees exist, an Executive CAC and a Full
  CAC

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Executive CAC

• Consists of four members
• The Associate Director for the Center
• A permanent carcinogenicity expert
• Supervisor from the presenting division
• A second Pharmacology Supervisor
• The Exec CAC meets every Tuesday and reviews from
  one to four protocols or carcinogenicity studies

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Full CAC

• Reviews studies when the Exec CAC cannot agree or
  when a drug sponsor makes a request
• Consists of
• The Associate Director of the Center
• The three associate Directors for the Offices
• The individual Pharmacology Supervisors for the
  Divisions
• The Full CAC meets very infrequently

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Full CAC Voting

• Does the CAC agree that the lung tumors in mice
  are relevant to human safety evaluation?
• Yes 16 No/Probably not 2 Dont know 2
• Does the CAC agree that (1) the liver tumors in
  male mice and (2) the vascular tumors in female
  mice are relevant to human safety evaluation?
• Yes 17 No 3
• Does the CAC agree that (1) hepatocellular
  adenomas and carcinomas in female rats, (2) the
  skin fibromas in female rats and (3) the brain
  gliomas in male and female rats are relevant to
  human safety evaluation?
• Yes 17 No - 3

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Summary

• Entecavir is a nucleoside analog which is a
  genetic toxin
• Entecavir is carcinogenic in male and female rats
  and mice
• Most of the tumors arise at high exposures in the
  animal studies
• The carcinogenic effect is relevant to the human
  safety evaluation
• Animal findings need to be balanced with the
  positive outcomes in the clinical trials and the
  nature of the disease