1. THE MICRODOSE CONCEPT Presenter: Professor Colin Garner BPharm PhD DSc FRCPath CEO, Xceleron Ltd, York, UK ® Xceleron Ltd – all rights reserved ©2004

2. A new product development tool kit ….is urgently needed to improve predictability and efficiency along the critical path ® Xceleron Ltd – all rights reserved ©2004

3. SUB-OPTIMAL PHARMACOKINETICS IS A COMMON REASON FOR DRUG FAILURE ® Xceleron Ltd – all rights reserved ©2004 OUR INDUSTRY CONTACTS STATE THAT HUMAN ADME/PK PREDICTION IS INCORRECT IN APPROXIMATELY 25-30% OF CASES!

4. THE AMS TECHNOLOGY ® Xceleron Ltd – all rights reserved ©2004

5. AMS counts atoms and not radioactivity For ease of understanding for biomedical researchers AMS data is expressed as DPMs AMS is the most sensitive analytical technique ever developed and has been used to measure drugs, metabolites, proteins, peptides and endogenous molecules ® Xceleron Ltd – all rights reserved ©2004 Carbon-14 = isotope of choice for AMS drug analysis Many other elemental isotopes can be analysed

6. Accelerator Mass Spectrometry (AMS) detects molecules at unprecedented levels of sensitivity 10 -9 g 10 -12 g 10 -15 g 10 -18 g 10 -21 g Liquid scintillation counting Competitor immunoassay Mass Spectrometry Accelerator Mass Spectrometry nanograms picograms femtograms attograms zeptograms Only AMS has the necessary analytical sensitivity for microdosing and ultralow label studies ® Xceleron Ltd – all rights reserved ©2004

7. RADIOACTIVE DOSES Typical radioactive dose in a conventional study = 80 to 100 µCi per person Typical radioactive dose in an AMS study = 100 nCi per person The average person contains ca 400 nCi naturally-occurring 14 C The average person contains ca 50 nCi naturally-occurring 40 K A banana contains about 1 nCi 40 K ® Xceleron Ltd – all rights reserved ©2004 FDA Regulatory issue ‘Is there a de minimis level of 14 C that can be administered to humans in the USA without animal dosimetry studies under 21CFRPart361?’

8. HUMAN MICRODOSING – GOING FROM LAB BENCH TO CLINIC IN FOUR MONTHS ® Xceleron Ltd – all rights reserved ©2004

9. WHAT IS MICRODOSING? Designed to obtain early human ADME/PK with minimal preclinical toxicology No pharmacological/toxic effect should be manifest No human safety/efficacy information obtained Requires radioisotopes and ultrasensitive analytical procedures eg AMS or PET ® Xceleron Ltd – all rights reserved ©2004

10. EARLY CANDIDATE SELECTION CURRENT PROBLEM Although many improvements in recent years, still limited information from in vitro and animal models to predict events in humans Lack of predictivity of allometric scaling? ® Xceleron Ltd – all rights reserved ©2004

11. CURRENT REGULATORY POSITION ® Xceleron Ltd – all rights reserved ©2004 FDA regulatory issue ‘Is the Agency minded to update 21CFR361 to include NCEs?’

12. WHAT IS A MICRODOSE? EMEA definition 1/100th of pharmacological dose based on animal data / in vitro systems OR a dose in or below the low microgram range but not to exceed 100 micrograms ® Xceleron Ltd – all rights reserved ©2004 FDA Regulatory issue ‘Can 21CFRPart361 include specific mention of microdosing as per the EMEA definition?’

13. TOXICOLOGY PACKAGE FOR MICRODOSE STUDIES Single dose 7 day acute study in rat with histopathology 3 male, 3 female, iv & route of human exposure Either 100 or 1000-fold safety factor 48 h, CVS in dog, 2 male 2 female, iv, telemetered or ECG, 100-fold safety factor Ames test - abridged protocol or OECD Abridged human lymphocyte chrom abs – abridged protocol or OECD In vitro metabolism studies rat and human plus plasma protein binding ® Xceleron Ltd – all rights reserved ©2004 FDA regulatory issue ‘What preclinical toxicology package could be used to support microdosing studies under 21CFR Part 361?’

14. ® Xceleron Ltd – all rights reserved ©2004 REGULATORY ISSUES TO BE CONSIDERED Can microdose studies on NCEs be covered by 21CFR Part361 Is AMS a technology that meets the Critical Path initiative of accelerating drug development? Are there scientific/regulatory reasons why AMS should not be used for all human volunteer radioactive studies (ALARA or ALARP) Are microdosing studies safer for FIH than current Phase I procedures? NEXT STEPS?