1. Consider Incorporating Respiratory Safety Pharmacology Measurements into Your Next Repeat Dose Toxicology Study September 14, 2012 Jeff Tepper, PhD, DABT Tepper Nonclinical Consulting TepperTox@gmail.com www.TepperTox.com

2. Respiratory Safety Pharmacology Objectives Primary Goal (Tier 1): Studies “to identify undesirable pharmaco- dynamic properties of a substance that may have relevance to human safety” on “functions which are acutely critical for life” prior to the first human exposure. Secondary Goals (Tier II): (1) to evaluate adverse effects observed in toxicology or clinical studies (2) to investigate the mechanism of adverse effects Tier II pulmonary function testing (PFT) which may require special procedures (e.g. anesthesia) and therefore are likely to be incorporated into stand alone studies or possibly in toxicology studies with satellite groups.

3. S7A Regulatory Guidance/Leeway It is important to adopt a rational approach when selecting and conducting safety pharmacology studies. The specific studies that should be conducted and their design will vary based on the individual properties and intended use. Moreover, the use of new technologies and methodologies in accordance with sound scientific principles is encouraged. Some safety pharmacology endpoints can be incorporated in the design of toxicology, kinetic, and clinical studies …

4. S7A Pulmonary Function Testing Guidelines 3. Respiratory System (2.7.3)... Respiratory rate and other measures of respiratory function (e.g., tidal volume or hemoglobin oxygen saturation) should be evaluated. Respiratory rate and tidal volume recommended (minute ventilation) Unanesthetized and unrestrained tests preferred If restrained, animals should be acclimated to testing procedure These requirements can be met in the context of a repeat dose GLP toxicology study Note: Tier I measurements are relatively insensitive, including newer less invasive techniques (telemetry and WBP), yet they are sufficient for detecting significant pulmonary effects.

5. Top 9 Reasons to Consider Incorporating PFT into Toxicology Studies 1. Regulatory acceptance (especially with biologics) has increased 2. Overall, better chance of finding and understanding any effect 3. Telemetry allows combined cardiopulmonary assessment 4. Correlative PK, Histo, Hematology, Coags & Clin. Chemistry 5. Serial measurements – acute and cumulative effects assessed 6. Larger range of doses – (hazard ID and risk assessment) 7. Larger N is available (increased sensitivity / statistical power) 8. Reduction in the overall number of animals for tox program 9. More efficient use of time, money and test article

6. Cases Where Incorporation into Toxicology Studies may be Encouraged Low or no level of primary or secondary pharmacology concern Target expression, activity or exposure not in lung, nerves, muscle When Cmax at steady state are very different then acute dosing Cumulative effects expected based on primary or secondary pharmacology of therapeutic/chemical class Delayed nonclinical or clinical PFT findings observed Local route of administration (inhaled/intranasal) Drug accumulates in lung Immunogenicity/antigenicity expected

7. Conclusions The appropriate safety pharmacology study should be based on the unique properties of the drug. Drugs that are of known low risk for pulmonary effects may be good candidates for incorporation in toxicology studies. Drugs at high risk of demonstrating pulmonary effects should probably be studied both in stand alone and repeat dose studies. As techniques improve, the integrative value of incorporating safety pharmacology into toxicology studies will have multiple benefits of improving our science and reducing the risk to clinical trial subjects.