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OUTLINE

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. General Recommendations for Nonclinical Studies Prior to Approval.

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OUTLINE

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  1. 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

  2. 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

  3. 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

  4. Overview:Results of the Nonclinical Studies • Audit of 2 pivotal studies identified significant deviations from Good Laboratory Practices [GLP] • Review is still ongoing

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

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