# Presentation: 254916

## Slide 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

## 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

## 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

## Overview:Results of the Nonclinical Studies

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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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