Presentation at the CRS Mtg 2002

Evaluation of the AERx System for the Pulmonary Delivery of

Recombinant Human Interferon alfa-2b to Healthy Subjects

Gul Balwani, Brooks Boyd, John Whatley, John Thipphawong, Richard Morishige, Jerry Okikawa, Babatunde Otulana, Emmanuel Tamchès, Thierry Buclin, Jerome Biollaz, François Spertini, Igor Gonda

CRS Meeting July 23, 2002

Introduction

• rH Interferon alfa-2b (MW of 19,265 Da)

• Specific activity = 2.6 x 10 8 IU/mg

• Indications

– Hepatitis B and C Infection

– Various cancers (Hairy cell leukemia, Malignant Melanoma, Follicular

Lymphoma)

• Therapy

– Chronic parenteral administration for at least six months

• Doses

– Hep. C: 3 MIU 3x/week

– Hep. B: 10 MIU 3x/week or 5 MIU/day

Advantages of Using AERx for Delivery of Interferon Alfa

• Non-invasive convenient therapy which should improve patient

compliance.

• Precise, reliable and efficient dosing similar to subcutaneous

injections.

CMC Goals

• Systemic Dose

• Blister Contents

• Fill Volume

• Target Concentration

• Stability

3-4 million units/dosage form

250 g or 65 million units

45 microliters

5.56 mg/ml

> 6 months at 5o C

Component Amount per DF Amount per ml

rH INF -2b, EP 0.2500 mg* 5.56 mg* Na2 HPO4 . 7 H2 O, USP Na H2 PO4 . 2 H2 O, USP

0.2613 mg 0.0234 mg

5.81 mg 0.52 mg

Polysorbate 20, NF 0.0450 mg 1.00 mg WFI, USP q.s. ad 45 L q.s. ad 1.0 ml

*Actual quantity weighed depends on the chemical assay Final pH adjusted to 7.5 using 25 mM solution of Na2 HPO4 / Na H2 PO4

Fill volume = 45 2.25 L ( 5 %)

Formulation Composition

Clinical Release Test Results

• Content uniformity: 99.9 % LC , 3.5 % RSD

• pH: 7.4

• Dimers: Less than limit of detection (0.1%)

• Emitted Dose & EDU: 65.9 %, 4.3 % RSD

• PSD: 2 μm MMAD, 1.35 GSD, 97 % FPF

• Endotoxin: < 0.6 EU/ml

• MLT: < 1 CFU/ml and absence of indicator organisms

• Bioassay: 1452 MIU/ml (65.34 MIU/DF)

Calculated Dose Levels

Label Claim: 250 μg/DF DF’s

Extrusion Contents (μg) (MIU)

Emitted Dose (μg) (MIU)

FPD (Lung Dose) (μg) (MIU)

1 Partial 250 65 47 12.2 46 12 1 Full 250 65 150 39 146 38 2 Full 500 130 300 78 291 76

65 MIU/DF is based on specific activity of 260 MIU/mg

Clinical Study

A Single-Center, Open-Label, Dose Escalation Study to

Compare the Safety, Pharmacokinetics, and

Pharmacodynamics of Subcutaneous and Inhaled Interferon

‑2b [IFN -2b] in Healthy Volunteers

Study Design (1)

Subjects Part A

SC Intron A Partial Dose 1 Blister 2 Blisters

3 10 MIU 46 mcg/12 MIU

3 10 MIU 146 mcg/38 MIU

8 10 MIU 291 mcg/76 MIU

Part B (Lung Dose using AERx)

Clinical Site: Hospital Beaumont, Lausanne, Switzerland

Sponsor: Aradigm Corp.

Washout period = 10 days

Study Design (2)

Blood Samples

• PK: 3 days (0, 30m, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 hrs).

• PD: 2 weeks (0, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168 hrs).

Endpoints

• PK – IFN 2b

• PD – 2’ 5’-AS, 2 microglobulin, neopterin

Study Design (3)

Safety

1. Methacholine challenge

(screening & end of study)

2. Pulmonary Function Tests (PFT)

(0, 30m, 60m, 90m, 3, 6 hrs. & end of study)

3. Labs: Hematology, biochemistry, urinalysis

(screening & end of study)

4. Adverse experiences

Results - Subjects

• 15 received IFN -2b SC (38.5 μg/10 MIU)

• 13 received AERx IFN -2b & completed Part B

(2 subjects dropped out after Part A)

• AERx IFN -2b

Dose n

46 μg/12 MIU 2

146 μg/38 MIU 3

291 μg/76 MIU 8

Results - Safety Summary

1. Adverse Events

41(33 mild, 8 moderate) after SC

22 (all mild) after AERx

2. No SAEs

3. ECG – no clinically relevant changes

4. Vitals – low grade fever in all groups (< 10 hours)

5. Lab – small variation in monocyte/lymphocyte count and

transaminases (expected after SC)

PK Results

0

10

20

30

40

50

60

70

80

90

0 6 12 18 24 30 36 42 48 54 60 66 72

Theoric_time (hr)

meandataIntronA10 MIU.pwo

Error

meandata inhaled EP2001 22.5MIU dose.pwo

Error

meandata inhaled EP2001 75MIU dose.pwo

Error

meandata inhaled EP2001 150MIU dose.pwo

Error

SC: 38 g (10 MIU)

Inhaled: 46 g (12 MIU)

Inhaled: 146 g (38 MIU)

Inhaled: 291 g (76 MIU)

Time (hr)

PK Results

Mean

PK

Parameter

SC

10 MIU

(%CV)

n=13

AERx

12 MIU

(%CV)

n=1

AERx

38 MIU

(%CV)

n=3

AERx

76 MIU

(%CV)

n=8

C max (IU/ml)

T max (h)

AUC 0-inf (h.IU/ml)

Frel to SC (%)

64

(37%)

6.8

(19%)

665

(40%)

-

3

10

34

ND

19

(20%)

10

(0%)

302

(38%)

12

35

(41%)

8.8

(21%)

514

(48%)

10

PD Results – β2 microglobulin

0.0

0.5

1.0

1.5

2.0

2.5

0 24 48 72 96 120 144 168

Time (hr)

meanb2-micro data 10 MIU intronA.pwo

Error

meanb2-micro data 150 MIU.pwo

Error

meanb2-micro data 75 MIU.pwo

Error

meanb2-micro data 22.5 MIU.pwo

Error

SC: 38 g (10 MIU)

Inhaled: 291 g (76 MIU)

Inhaled: 146 g (38 MIU)

Inhaled: 46 g (12 MIU)

PD Results – 2-5AS

0

500

1000

1500

2000

2500

0 24 48 72 96 120 144 168

Time (hr)

mean 2-5AS data 10 MIU IntronA.pwo

Error

mean 2-5ASdata 150 MIU.pwo

Error

mean 2-5AS data 75 MIU.pwo

Error

mean 2-5AS data 22.5 MIU.pwo

Error

SC: 38 g (10 MIU)

Inhaled: 291 g (76 MIU)

Inhaled: 146 g (38 MIU)

Inhaled: 46 g (12 MIU)

Relationship Between Inhaled Doses and

Corresponding AUC

y = 1.9236x - 26.36

R2 = 0.9704

0100200300400500600700

0 100 200 300 400

Lung Dose (mcg)

AU

C (0

to in

f)

Conclusions

• AERx IFN bioavailability is 10-12 % relative to IFN SC.

• PD response was found to be similar for all doses of AERx IFN and 10 MIU

of IFN given SC thereby allowing lower dosing by pulmonary route.

• Lower incidence and severity of adverse events by the pulmonary route

compared to SC.

– Local skin reaction seen by SC can be eliminated by pulmonary route.

• AERx intersubject variability similar to SC.

Acknowledgements

• Aradigm Corporation, Hayward, CA

– Dr. Stephen Farr, VP Research & Development

– Beth Mallory

– Evelyn Gabatan

– Christine Inose

– Lawrence Linn

• Division of Clinical Pharmacology, CHUV, Lausanne, Switzerland

• Division of Immunology and Allergy, CHUV, Lausanne, Switzerland

• Triskel Integrated Services, Geneva, Switzerland