1. Dose Selection in Pharmaceutical Development Eliseo Salinas, MD, MSc Chief Scientific Officer Shire Pharmaceuticals

2. © Shire 2  Context: drivers for dose selection  Stepwise approach for dose selection  A case study Summary

3. © Shire 3 Dose-selection / Definition Choice of a dose / range of doses supposed to include the ultimately safe and effective dose / range of doses.

4. © Shire 4 Grabowski H, Vernon Jm DiMasi JA: PharmacoEconomics 2002; 20 Suppl 3, 11-29 Cash flow over the product life cycle Market introduction Peak year salesGeneric entry

5. © Shire 5 Grabowski H, Vernon Jm DiMasi JA: PharmacoEconomics 2002; 20 Suppl 3, 11-29 Cash flow over the product life cycle Market introduction R&D costsSales

6. © Shire 6 Grabowski H, Vernon Jm DiMasi JA: PharmacoEconomics 2002; 20 Suppl 3, 11-29 Cash flow over the product life cycle IP protection Shift to the left

7. © Shire 7 IP protection Cash flow over the product life cycle (-3 years) Shorten clinical development

8. © Shire 8 phase I Healthy volunteers (small n) -Initial tolerability -PK Drug interactions Special pharmacology phase II Patients (small n) -Initial efficacy -Initial tolerability -Initial safety Clinical development phase III Patients (big n) -Pivotal efficacy -Pivotal safety DATA? registration

9. © Shire 9 Cost and duration of clinical development Mean duration (months) Mean out-of-pocket cost (millions 2000 dollars) Phase I 21.6 mo $15.2M Phase II 25.7 mo $23.5M Phase IIII 30.5 mo $86.3M DiMasi JA et al, Journal of Health Economics 22 (2003), 151-185

10. © Shire 10 Drug development across therapy areas DiMAsi et al, Drug Information Journal, 2004, vol 38, pp 211-223

11. © Shire 11 Drug development mantra  Duration of treatment?  Number of doses?  Need for titration?  Ideas re dose-response? Start with the end in sightHow will we design our pivotal phase III?

12. © Shire 12 Dose response: the case of antipsychotics Davis JM et al, J Clin Psychopharmacol 2004, 24:192-208

13. © Shire 13 Single ascending dose (SAD) in healthy volunteers Search for a maximal tolerated dose (MTD) Cohorts Dose A B C E F I G X X MTD D Significant AEs H J

14. © Shire 14 Tolerability or need for titration: Multiple Ascending Dose (MAD) Cohort ACohort BCohort C MTD single dose

15. © Shire 15 How to select doses for the SAD?  Toxicology: initial dose in SAD as a fraction (1/10) of No Adverse Event Level (NOAEL) dose (FDA guidelines)  Allometric scaling: target concentration in relevant animal model corrected by total body weight  Physiologically Based Pharmacokinetic Modelling (PBPK): modelling of distribution in several tissues and blood circulation

16. © Shire 16 Dose response relationships and dose selection ABC A B C A C B B C AB C Was true MTD reached?

17. © Shire 17 A case study: desvenlafaxine succinate (DVS)  Case study based on public information only  DVS: active metabolite of venlafaxine (Effexor ® )  Extensive knowledge of animal and human pharmacology of parent

18. © Shire 18 Effexor ® : pharmacology  Mechanism of action  Potent inhibitor reuptake of serotonin and norepinephrine  Weak inhibitor of dopamine reuptake  Dosing:  75 to 375 mg / day  “… certain patients may respond more to higher doses …” (Physician’s Desk Reference)  Dose-dependent effects on blood pressure (PDR)

19. © Shire 19 DVS pharmacology Deecher AC et al, The Journal of Pharmacology and Experimental Therapeutics, 2006, 318, 657-665  Good affinity for serotonin, norepinephrine and dopamine transporters

20. © Shire 20 Deecher AC et al, The Journal of Pharmacology and Experimental Therapeutics, 2006, 318, 657-665 DVS pharmacology (cont’d)  Potent inhibitor of reuptake of serotonin and norepinephrine  Weak inhibitor reuptake of dopamine

21. © Shire 21  Single Ascending Dose (SAD) 150 mg, 225 mg, 300 mg, 450 mg, 600 mg, 750 mg, 900 mg / 24h n=10 (6 DVS, 2 venER 150, 2 pcb) Max tolerated single dose: 750 mg/24h  Multiple Ascending Dose (MAD) 300 mg, 450 mg, 600 mg / 24h n=12 (9 DVS, 3 pcb) Max tolerated multiple dose: 450 mg DVS: SAD and MAD findings [ASCPT abstract PII-130] Clin Pharmacol Ther 2005, 77(2) p84 [ASCPT abstract PII-122] Clin Pharmacol Ther 2005, 77(2) p82

22. © Shire 22 * * * * DVS: efficacy results / dose finding study A  18-75 year old patients with depression  8 week  Fixed doses: 200 mg / 400 mg / placebo  N=375 Septien-Velez L et al, Int Clin Psychopharmacol 2007, 22:338-347

23. © Shire 23 DVS: efficacy results / dose finding study B  18-75 year old patients with depression  8 week  Fixed doses: 100 mg / 200 mg / 400 mg / placebo  N=480 * * ns * * * Kaneth J et al, Future Neurology, 2007, 2, 361-371

24. © Shire 24 (2) Kaneth J et al, Future Neurology, 2007, 2, 361-371 Safety in pivotal DVS studies A (1) and B (2) Placebo Nausea Supine pulse rate 14 (11) Systolic BP Diastolic BP QTc (Bazett) -1.43 -1.39 -1.03 -0.36 200 mg 57 (46) 1.79 0.85 0.91 2.53 400 mg 63 (50) 5.79 1.19 1.35 7.78 Placebo 10 (8) 0.15 0.23 0.44 NR 100 mg 41 (35) -0.03 2.96 2.21 4.64 200 mg 36 (31) 1.06 3.62 2.84 6.66 400 mg 47 (41) 4.19 4.05 3.41 7.25 (1) Septien-Velez L et al, Int Clin Psychopharmacol 2007, 22:338-347

25. © Shire 25 DVS: summary of regulatory history  Dec 22, 2005: Wyeth submits NDA for depression  Sept 8, 2006: FDA’s Psychopharmacologic Drugs Advisory Committee to discuss DVS  Jan 22, 2007: FDA issues Approvable letter for DVS (requires low dose studies)  August 2007: Wyeth submits complete response to approvable letter (includes two additional positive depression studies at 50 and 100 mg).  Feb 29, 2008: FDA Approves DVS for the Treatment of Adult Patients with Major Depressive Disorder

26. © Shire 26  Predictability of animal models  Pharmacokinetic / pharmacodynamic relationships  Species-dependent toxicity  Species-dependent tolerability  Only a limited number of “shots” to a target in the darkness  Dose selection remains the most challenging decision in drug development Challenges in dose selection for clinical development

27. Dose Selection in Pharmaceutical Development Eliseo Salinas, MD, MSc Chief Scientific Officer Shire Pharmaceuticals