1. NMF 3/6/03 Susan Galbraith, MB BChir PhD Vice President Clinical Discovery Oncology & Immunology Phase 0 Trials Why aren’t they more widely used by industry?

2. NMF 3/6/03 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 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. NMF 3/6/03 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 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. NMF 3/6/03 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 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. NMF 3/6/03 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 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. NMF 3/6/03 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 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. NMF 3/6/03 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 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