Integrating functional CNS observations into toxicology studies: Preliminary Results from An Industry Survey Simon Authier, DVM, MBA, PhD Director - Safety Pharmacology and Veterinary Science CIToxLAB North America

Agenda Introduction Preliminary results from an Industry Survey Expert panel presentations – Pros: Mary Jeanne Kallman, PhD (Covance) – Cons: Will Redfern (AstraZeneca) Open discussions Closing remarks

Introduction: Methodologies Functional Observation Battery in Rodents: Widely accepted Functional Observation Battery in Large Animals: – Canines Gad SC & Gad SE. A functional observational battery for use in canine toxicity studies: development and validation. Int J Toxicol Nov-Dec;22(6): Tontodonati M et al. A canine model used to simultaneously assess potential neurobehavioural and cardiovascular effects of candidate drugs. J Pharmacol Toxicol Methods Sep;56(2): – Non human primates Authier S. et al., Functional observation battery in nonhuman primates with continuous intracerebral infusion. J Pharmacol Toxicol Methods Sep-Oct;66(2):162. Gauvin DV, Baird TJ. A functional observational battery in non-human primates for regulatory-required neurobehavioral assessments. J Pharmacol Toxicol Methods Sep;58(2): – Minipigs van der Laan JW, et al.; RETHINK Project. Regulatory acceptability of the minipig in the development of pharmaceuticals, chemicals and other products. J Pharmacol Toxicol Methods Nov;62(3): Authier S et al., Safety Pharmacology in the Göttingen minipig: Cardiovascular, Respiratory and Neurological Investigations. Annual Meeting of SOT 2012, San Francisco

Preliminary Industry Survey Results Total of 361 participants

Preliminary Industry Survey Results

Slides of expert panel members

Questions for open discussions Based on your opinion, S7A safety pharmacology endpoints in regulatory toxicology studies are generally appropriate for: – CNS safety pharmacology for small molecules ? – CNS safety pharmacology for large molecules ? – As a standalone study?

Questions for open discussions In your organization, has the ability to add safety pharmacology endpoints onto regulatory toxicology studies had any of the following consequences? – Allowed you to manage safety risk more effectively? – Data contributed to the halting the progression of a compound? – Data addressed a specific concern and supported the continuation of a compound?

Questions for open discussions Based on your experience, please state any disadvantages of safety pharmacology investigations in toxicology studies? Based on your experience, please state any advantages of safety pharmacology investigations in toxicology studies?

Questions for open discussions Have you received regulatory feedback on inclusion of respiratory safety pharmacology in toxicology studies?

Thank you for your time and participation! Looking forward to see you in Phoenix for the 2012 Annual SPS meeting