OUTLINE

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OUTLINE

• General recommendations for nonclinical studies
  to support an NDA
• Recommendations for nonclinical studies to
  support an NDA for GL 701
• Overview of nonclinical study results for GL 701
• DHEA and carcinogenicity

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General Recommendations for Nonclinical Studies
Prior to Approval

• Based on ICH Guidance M3
• Single and repeat dose toxicology studies
• Pharmacokinetic/toxicokinetic studies
• Safety pharmacology studies
• Reproductive toxicology studies
• Genetic toxicology studies
• Carcinogenicity studies

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Recommendations for Nonclinical Studies for GL 701

• Six-month repeat dose toxicology study in dogs to
  include toxicokinetic endpoints
• Standard battery of reproductive toxicity studies
• Standard battery of genotoxicity studies

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OverviewResults of the Nonclinical Studies

• Audit of 2 pivotal studies identified significant
  deviations from Good Laboratory Practices GLP
• Review is still ongoing

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Overview Results of the 6-Month Repeat Dose Dog
Study

• Clinical Signs
• Treatment-related vomiting
• Target Organs
• Reproductive organs
• Liver
• Adrenal gland
• Metabolic Effects
• Cholesterol lowering

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Overview Reproductive Toxicity Studies

• Fertility
• Females - interruption of estrous cyclicity and
  decreased number of corpora lutea
• Embryofetal Development
• Rat - Decreased embryofetal viability, increase
  in skeletal variation

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Overview Reproductive Toxicity Studies

• Pre and Postnatal Development
• Fetotoxicity - increased incidence of 100
  resorptions, decreased birth weight
• Postnatal toxicity - decreased pup weight through
  lactation period

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Overview Genetic Toxicology Studies

• Negative
• In the Ames assay
• In an in vivo mouse micronucleus assay
• Positive
• In an in vitro Chinese hamster ovary cell
  chromosomal aberration assay

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Recommendations for Carcinogenicity Studies for
GL 701

• No studies to address carcinogenicity were
  conducted prior to submission of NDA based on an
  agreement between the Division and Genelabs
• Labeling of prasterone would be similar to that
  for estrogens and androgens

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Carcinogenic Potential of DHEA Summary of
Nonclinical Literature

• Reports indicate that DHEA has been shown to be
  chemoprotective or carcinogenic depending on the
  model
• DHEA may be inhibitory or stimulatory to hormone
  sensitive tumors
• Literature suggests that DHEA is less potent than
  its androgenic/estrogenic metabolites

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Carcinogenic Potential of DHEA Summary of
Nonclinical Literature

• The apparent inhibition of tumor development
  demonstrated in animals may be due to both
  hormonal and nonhormonal activity of DHEA

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Carcinogenic Potential of DHEA Summary of
Nonclinical Literature

• Hepatocarcinogen in the rat and trout
• Hepatocarcinogenicity in the rat is associated
  with peroxisomal proliferation
• Increased incidence of granulosa cell tumors in
  genetically predisposed mice

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Carcinogenic Potential of DHEA Summary of the
Human Literature

• No randomized well-controlled trials
• There is a theoretical but unproven potential
  increased risk of cancer
• Similarly to androgenic and estrogenic compounds,
  it is anticipated that it will be difficult to
  define the carcinogenic potential of DHEA