P r e c l i n i c a l d e v e l o p m e n t c o n s i d e r a t i o n s f o r t h e p u l m o n a r y d e l i v e r y o f d r u g s a p p r o v e d b y o t h e r r o u t e s

C h e t L e a c h

L i f e S c i e n c e s R e s e a r c h a n d D e v e l o p m e n t

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 HFATM (AiromirTM) versus Albuterol CFC

Same drug, different propellant

Same amount of drug delivered

Same particle size distribution

Improved dosing characteristics

Proventil HFA

Ventolin

Proventil-HFAPreclinical 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

QVARTM (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

QVARPreclinical 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

PharmacokineticsModel predictions for QVAR

Mucocilaryclearance

Projected Serum Levels Based on Deposition Results

Beclovent - 100a QVAR - 100a

Oral depositionb 95g 20g 30g 6gc

Lung depositionb 5g 5g 60g 60g

Serum Total 25g 66g

Ratio 1 2.6:

a assumes 100g of beclomethasone dipropionate is delivered to the patientb 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 StudySerum Concentrations of BDP After

Single Inhaled Doses

0

200

400

600

800

0 5 10 15 20 25 30

Time Post Initial Inhalation (hours)

Ser

um B

eclo

met

haso

ne

Con

cent

rati

on (

pg/m

l)

200 mcg HFA-BDP400 mcg CFC-BDP

Regression analysis of change from baseline in FEV1 as % predicted at

week 626

24

14

16

18

20

22

100 400 800150

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 FEV1 as % predicted

Long-term asthma control:breakthrough asthma following 2:1

switch

HFA-BDPCFC-BDP

0

20

40

60

80

100

Day1

Wk4

Wk8

Mth4

Mth6

Mth8

Mth 10

Mth12

% patients with no asthma related adverse events

Kaplan Meier plot

Urinary Free Cortisol:Percentage change from baseline in 24hr UFC

-100

-80

-60

-40

-20

0

20

40

60

80

100

HFAPlacebo

HFA BDP200 mcg

HFA BDP400 mcg

HFA BDP800 mcg

CFC BDP800 mcg

Percentagechangefrombaseline in24hr UFC

* **

* Indicates significant mean difference from Placebo

QVARPreclinical 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

Natural Human Bioavailability of Insulin

Based on various published studies

30

25

20

15

10

5

0Oral Nasal Pulmonary

Bioavailability

relative to

SC injection

(%)

InsulinPreclinical / 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

0.01

0.1

1

10

100

0 4 8 12 16 20 24

Time postdose (hr)

Ser

um

leu

pro

lide

(ng

/ml)

IV

INHL

iiiii

PulmoSphere

Particles

22 µ µmm•Hollow•Porous•Ultra low density

Self-Assembling Structures in Water

LeuprolidePreclinical / Clinical Issues

Larger local lung concentrations than previously seen

Antibody question

DSPC, DPPC excipients

(normal components of lung surfactant)

0

100

200

300

400

0

20

40

5001000150020002500

0 2 4 6 8 10 12 14

0

100

200

Pla

sm

aC

onc

(ng/m

L)

Time After Dosing (hr)

Plasma

Lavag

eC

onc

(ng/m

L)

Lung

LavageInhalation IVMean InhalationMean IV

Lun

gC

onc

( g/g

)

Inhalation versus i.v. of Antibiotic A in rats

Antibiotic A inhalation in Dogs

0

100

200

300

400

500

600

700

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

0

10

20

30

40

50

Low Dose Mid Dose High Doseng

/ m

L P

lasm

a

Time After Start of Dosing (days)

Plasma t1/2 = 28 hours

Day 1 Day 14 Day 29

g/g

Lun

gA

nti

bio

tic

Co

nce

ntr

atio

n

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

0

0.2

0.4

0.6

0.8

0 4 8 12 16 20 24

Hours (time after end of inhalation)

Se

rum

An

tib

ioti

c B

(u

g/m

l)

PulmoSphere Antibiotic B, 85 mg

Nebulized Antibiotic B, 300 mg

Antibiotic B in Humans

Minutes to Dose

Dry Powder Nebulizer

0

2

4

6

8

10

12

14

16

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