Susan Galbraith, MB BChir PhD Vice President Clinical Discovery Oncology & Immunology

1. Phase 0 Trials Why aren’t they more widely used by industry? Susan Galbraith, MB BChir PhDVice PresidentClinical DiscoveryOncology & Immunology

2. Questions which Phase 0 trials could answer • Tissue distribution after microdosing • Useful for PET imaging agent development • Preparation for receptor occupancy studies • Comment • Clear utility to such studies • They form relatively small proportion of pharmaceutical industry studies

3. Questions which Phase 0 trials could answer • Mechanism of Action determination • Enzyme or receptor binding or inhibition • Comment • Need to be in pharmacologically active dose range • This question is routinely asked / answered in studies in NHVs - SAD or MAD 7 to 14 day Phase I trials together with PK and safety assessments using traditional IND • Safety margin required in exploratory IND for cancer patients would generally permit dosing in NHVs with exception if compound is clastogenic • NHV SAD trials can accrue a cohort of 8 subjects per week – whole study completed across wide dose range in 8 weeks

4. Questions which Phase 0 trials could answer • Mechanism of Action determination (contd) • Enzyme or receptor binding or inhibition • Comment • Doing such studies in cancer patients raises ethical and accrual issues but could have advantage if PD effects only likely to be seen in tumor tissue • For oncology targeted agents TI may frequently not permit dose escalation into pharmacologically active range if exploratory IND dose range guidance applied • Maximum dose - to achieve up to ½ of the AUC at the NOAEL in the 2-week rodent study, or the AUC in the dog at the rat NOAEL, whichever is lower

5. Questions which Phase 0 trials could answer • Selection of most promising lead from a group of compounds • By testing for more desirable PK/PD characteristics • Comment • Assumes lack of predictability for such characteristics in preclinical models • Infrequently have more than one compound as potential clinical candidates which can’t be prioritized based on preclinical screening tests • Comments about dose range and population (NHVs vs cancer patients) still apply

6. Additional Points • Would use of Phase 0 trials speed drug development? • Time to FIH could be faster with Phase 0 plan -but is not major metric of interest – time to PoC is more relevant • Traditional toxicology package and traditional IND filing still required for subsequent trials • Could be used for early No Go, but in event of Go decision doing Phase 0 will add time and cost

7. Summary • Definite utility to microdosing trials for imaging agent development • Use of NHVs for SAD studies under traditional IND gains most of advantage that a Phase 0 PD/MoA trial in cancer patients could provide in a shorter time • Exception is ability to obtain tumor PD • Some circumstances where Phase 0 trials could be used in oncology for PD/MoA but TI often limits this • Ability to transition to traditional IND would increase incentive to use this tool