1. PHARMACODYNAMIC TESTING FOR ORALLY INHALED DRUGS: CORTICOSTEROIDS Staffan Edsbäcker, Assoc.Prof. University of Lund and Experimental Medicine, AstraZeneca, Lund SE/Expmed/990601

2. Pharmacodynamic Testing Proof of concept –new steroid molecules –new antiinflammatory agents Therapeutic equivalence / comparability –modified/improved formulation –generic formulation Product comparisons –marketed formulations SE/Expmed/990601

3. Proof-of-concept Efficacy vs placebo and/or comparator –choose clinically relevant surrogate with little variability in validated model Safety vs placebo and/or comparator –cortisol suppression Confounding Factors –unique kinetics? –selective mode of action? SE/Expmed/990601

4. Surrogate markers a clinical measurement statistically associated with a clinical outcome with current knowledge is believed to share a causal mechanism with the clinical outcome Surrogates should be - Specific (lung deposition, biopsy eosinophiles) - Validated (BHR, sputum eosinophiles) - Proximal (FEV1, morning PEF), - Practical (NO, U-LTE 4 ) but none is perfect! SE/Expmed/990601

5. Models Selected patient groups –disease severity (e.g. steroid dependent) –lung function (e.g. reversibility, % predicted) –BHR, Sputum eosinophiles, NO etc. Allergen challenge –dual reaction –late reaction SE/Expmed/990601

6. Hargreave et al, Inhaled Glucocorticoids in asthma, 1997, 133 SE/Expmed/990601

7. Dose-related Effect of Budesonide on FEV 1 and Exhaled NO in Asthma 100  g (n=9) Placebo (n=6) 400  g (n=7) 0123456 -75 -50 -25 0 25 50 75 * terbutaline budesonide/placebo + terbutalineterbutaline ** Treatment (weeks) Exhaled NO (% change) 0123456 -15 -10 -5 0 5 10 15 20 Treatment (weeks) FEV 1 (% change) FEV 1 NO terbutaline budesonide/placebo + terbutalineterbutaline 100  g Placebo 400  g Jatakanon, Kharitonov, Lim and Barnes, Thorax 1999, 54: 108 p<0.05 vs 100 ** * p<0.01 vs 100 gg gg SE/Expmed/990601

8. Mean change from baseline Morning PEF (L/min) Baseline0-22-44-66-88-1010-12 0 10 20 30 40 50 60 Two-week interval Therapeutic Equivalence

9. SE/Expmed/990601 Two doses of Pulmicor t Turbuhaler vs Placebo in mild (moderate) asthma Placebo Budesonide 200 µg BID Budesonide 400 µg BID Mean change from baseline Morning PEF (L/min) Baseline0-22-44-66-88-1010-12 0 10 20 30 40 50 60 Two-week interval Kemp et al, 1994

10. SE/Expmed/990601 Inhaled Fluticasone Propionate 0 5 10 15 20 FP 100 n=129 FP 200 FP 400FP 800 n=132 n=133 L/min  PEF BDP 400 Pedersen B & Dahl R, 1993

11. SE/Expmed/990601 Pedersen B & Dahl R et al, 1993 0 100 200 300 400 FP 100 n=129 BDP 400 n=126 FP 200 n=132 FP 400 n=132 FP 800 n=133 L/min p = 0.001 PEFRchange 14 L/min 365370 371 374 379 Inhaled Fluticasone Propionate Mean Morning PEFR

12. SE/Expmed/990601 The Confidence Interval Approach Treatment difference No diff. Predetermined limits

13. FDA Pulmonary-Allergy drugs advisory meeting, 1995 Comparison of two CFC pMDI formulations SE/Expmed/990601

14. Therapeutic Equivalence Inhaled Corticosteroids Recommendations for pharmacodynamic testing Patients –strict inclusion criteria Design –dose scaling Endpoint –composite EOS, NO and BHR score  dose 10 2 10 3  d/22d   * SE/Expmed/990601

15. Simulated Trial Outcome Morning PEF NO 100 pat/group 500 pat/group50 pat/group 0/100 succesful 21/100 succesful 35/100 succesful 2d ½d 2d ½d 2d ½d SE/Expmed/990601

16. Asthma Clinical Research Network (1) Dose of Inhaled Corticosteroids with Equisystemic Effects (DICE) –estimate dose response for adrenal suppression for –BDP pMDI+spacer –TAA pMDI+spacer –FLU pMDI +spacer –BUD TBH –FP pMDI –FP Diskhaler –156 mild/moderate asthmatics; incrementing bid doses, 1 week/dose, 20 patients/group

17. SE/Expmed/990601 Asthma Clinical Research Network (2) Measuring Inhaled Corticosteroid Efficacy (MICE) –Estimate efficacy at equivalent biosystemic effects –BDP pMDI+spacer –TAA pMDI+spacer –FLU pMDI +spacer –BUD TBH –FP pMDI+spacer –FP Diskhaler –Select three doses/steroid (5-10%, 25-30% and 50% suppression) –300 Moderate asthmatics: 2 wks run-in, 6 wks low dose 6 wks high dose, 2 wks prednisone. FEV1 primary variable. –Pilot study with two products

18. Pharmacodynamic Testing of Inhaled Corticosteroids - Conclusion If carefully designed and executed –essential part of proof-of-concept –appropriate for equivalence testing –valuable for drug product comparisons Special care needs to be put on –selection of patients –study design –selection of surrogate marker(s) SE/Expmed/990601

19. Acknowledgements Per Larsson, PhD, biomathematician, AstraZeneca (Statist. Med. 18, 629-641 (1999)) SE/Expmed/990601