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

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?

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

Proventil HFA Ventolin

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

Clinical Efficacy Study

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

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

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

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

Pharmacokinetics Model predictions for QVAR Mucocilary clearance

Projected Serum Levels Based on Deposition Results Beclovent a QVAR 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

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

Regression analysis of change from baseline in FEV 1 as % predicted at week CFC-BDP Qvar Total daily dose (mcg/day) Relative dose ratio 2.6 (95% CI ) 2.6 Change from baseline in FEV 1 as % predicted

Long-term asthma control: breakthrough asthma following 2:1 switch HFA-BDP CFC-BDP 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

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

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

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

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

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

Leuprolide PulmoSphere ™ DPI

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

Self-Assembling Structures in Water

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

Inhalation versus i.v. of Antibiotic A in rats

Antibiotic A inhalation in Dogs 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

Phase-1 Clinical Study of Antibiotic B Hours (time after end of inhalation) Serum Antibiotic B (ug/ml) PulmoSphere Antibiotic B, 85 mg Nebulized Antibiotic B, 300 mg

Antibiotic B in Humans Minutes to Dose Dry PowderNebulizer

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)

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