2. Contents General considerations for pulmonary drugs Case Study - Proventil-HFA Case Study – QVAR Lung delivery of peptides/proteins Lung delivery of i.v. antibiotics Conclusions

3. General Preclinical Considerations Has the drug been to the site before? Is the local concentration at the new site higher than before? Are the usual metabolic pathways present in the new site? Are there new susceptible cell types (e.g. growth factor issues)? Will new or existing excipients cause problems (e.g. bronchospasm, membrane disruptors)? Will neutralizing or anaphylactic antibodies form?

4. Proventil HFA TM (Airomir TM ) versus Albuterol CFC Same drug, different propellant Same amount of drug delivered Same particle size distribution Improved dosing characteristics

5. Proventil HFA Ventolin

6. Proventil-HFA Preclinical Program (registered in 40 countries) Inhalation range-finding study in rats Inhalation range-finding in dogs 28-Day inhalation study in rats 28-Day inhalation study in dogs 90-day inhalation study in rats Inhalation teratology study in rats

7. Clinical Efficacy Study

8. Proventil HFA Preclinical Conclusions No preclinical surprises in two species No PK/ADME clinical surprises No efficacy surprises SO no further preclinical studies necessary

9. QVAR TM (HFA-BDP) versus CFC-Beclomethasone (CFC-BDP) Same drug, different propellant Different amount of drug delivered Different particle size distribution Improved dosing characteristics

10. Human Deposition Pattern QVAR 31%94%Oral Lung 59%4% CFC-BDP 8%1%Exhaled 1.1 microns 3.5 microns

11. QVAR Preclinical Program (registered in 40 countries) Inhalation range-finding study in rats Inhalation range-finding in dogs 14-Day inhalation study in rats 14-Day inhalation study in dogs 12-month inhalation study in dogs Inhalation teratology study in rats

12. Pharmacokinetics Model predictions for QVAR Mucocilary clearance

13. Projected Serum Levels Based on Deposition Results Beclovent - 100 a QVAR - 100 a Oral deposition b 95  g 20  g30  g6gc6gc Lung deposition b 5g5g 5g5g60  g Serum Total 25  g66  g Ratio 12.6: a assumes 100  g of beclomethasone dipropionate is delivered to the patient b assumes an oral bioavailability of 21% and a lung bioavailability of 100% c the formula represents amount deposited serum based on bioavailability

14. Phase 1 Clinical Study Serum Concentrations of BDP After Single Inhaled Doses

15. Regression analysis of change from baseline in FEV 1 as % predicted at week 6 26 24 14 16 18 20 22 100400800150 CFC-BDP Qvar Total daily dose (mcg/day) Relative dose ratio 2.6 (95% CI 1.1-11.6) 2.6 Change from baseline in FEV 1 as % predicted

16. Long-term asthma control: breakthrough asthma following 2:1 switch HFA-BDP CFC-BDP 0 20 40 60 80 100 Day 1 Wk 4 Wk 8 Mth 4 Mth 6 Mth 8 Mth 10 Mth 12 % patients with no asthma related adverse events Kaplan Meier plot

18. QVAR Preclinical Conclusions No preclinical surprises in two species No PK/ADME clinical surprises No efficacy surprises SO no further preclinical studies necessary

19. Proteins/Peptides There are numerous peptides with significant therapeutic activity in every field of medicine BUT, they have serious delivery problems –Need to inject –Time of action too short –Native structures too susceptible to peptidases

20. Local Lung versus Systemic Delivery Rule of thumb is that 2-5% of the i.v. dose reaches the lungs The other 95% adds to unwanted side- effects

22. Insulin Preclinical / Clinical Issues Insulin is present in virtually every cell Larger local lung concentrations than previously seen Insulin is a growth factor Insulin by any route induces antibody formation

23. Leuprolide Analog of LHRH Treatment of endometriosis Treatment of prostate cancer Side effects inhibit its use

24. Leuprolide PulmoSphere ™ DPI

25. PulmoSphere  Particles 2 µm2 µm2 µm2 µm Hollow Porous Ultra low density

26. Self-Assembling Structures in Water

27. Leuprolide Preclinical / Clinical Issues Larger local lung concentrations than previously seen Antibody question DSPC, DPPC excipients (normal components of lung surfactant)

28. Inhalation versus i.v. of Antibiotic A in rats

29. Antibiotic A inhalation in Dogs 18202224262830 0 10 20 30 40 50 Low Dose Mid Dose High Dose ng / mL Plasma Time After Start of Dosing (days) Plasma t1/2 = 28 hours Day 1 Day 14 Day 29  g/g Lung Antibiotic Concentration Lung Tissue t1/2 = 19 days 4 orders of magnitude delta between lung and plasma Plasma likely to be undetectable at doses targeting MICs in lung

30. Phase-1 Clinical Study of Antibiotic B 0 0.2 0.4 0.6 0.8 04812162024 Hours (time after end of inhalation) Serum Antibiotic B (ug/ml) PulmoSphere Antibiotic B, 85 mg Nebulized Antibiotic B, 300 mg

31. Antibiotic B in Humans Minutes to Dose Dry PowderNebulizer 0 2 4 6 8 10 12 14 16

32. Summary A route change to inhalation can offer: –Faster onset –Higher bioavailability –Freedom from injections –Less side effects Preclinical requirements should be unique to each new change in route Preclinical programs should stress the exploration of known differences, not unsubstantiated speculation The fear of unknown and/or unreasonable preclinical and clinical requirements keeps many new routes for drug administration economically unattractive (especially for non-blockbuster category drugs)

33. Future Biotech Inhalers Insulin Growth factors (local & systemic) Interferons Lung surfactants Monoclonal antibodies Receptors Viral vectors