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Insulin Antibodies Associated with Technosphere® Insulin (TI)

Wen Yu, Mark T. Marino, James P. Cassidy, Anders H. Boss, Samuel Fineberg

©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 2

Overview & Objectives

Controlled Phase 2/3 Trials TI Comparators

Type 1 614 599

Type 2 1733 1398

All diabetes 2347 1997

1. What are the insulin antibody (IAB) changes?

2. Clinical significance?

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Presenter Disclosure Information

The American Diabetes Association requires the following disclosure to the participants:

Dr. Wen Yu is an employee and shareholder of MannKind Corporation (sponsor).

No clinical recommendations will be offered in this presentation, the content of which will be limited to

scientific data and research results.

©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 4

Technosphere® Insulin (AFREZZA™)

pH < 6as

AFREZZA™

pH > 6 in the lungs

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IABs: Brief Background

Historical concern and clinical significance

Many factors at play1

e.g. Insulin purity, structure, insulin dose, formulations, patient genetic determinants, diabetes types, age, site of administration, etc.

All other pulmonary human insulins have been show to produce greater insulin antibody response over subcutaneous insulins but with no adverse clinical consequences2

e.g., median increase of IAB in pooled Exubera patients after 24 weeks: 10x (type 1) vs. 2x (type 2)

1. Fineberg et al, Endocrine review 2007

2. Fineberg et al, DST 2007

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IAB Measurement Methodology

Validated quantitative Radioimmune Assay (RIA) was performed by Bio Analytical Research Corporation (BARC)

The class of antibody measured was IgG

No attempt was made to differentiate low vs. high affinity binding

Units reported is “Kronus units of insulin antibody/mL”

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What Are The IAB Changes?

Study No./ Diabetes Type n

Baseline(U/mL)

Week 26(U/mL)

Week 52(U/mL)

009 / Type 1

TI 283 7.2(0.8, 531.1)

58.6(0.8, 726.4)

48.2 (1.9, 933.2)

sc insulin 260 6.6(0.8, 200.0)

8.2(0.8, 200.0)

8.7(0.8, 192.4)

102 / Type 2

TI 300 6.1(0.8, 138.6)

14.9(0.8, 586.5)

14.5(0.8, 532.5)

sc insulin 309 5.6(0.8, 141.3)

8.9(0.8, 190.5)

8.7(0.8, 197.3)

Median Insulin Antibodies (Kronus® Units/mL)

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IAB Temporal PatternPooled Safety Population, Type 1 and Type 2 DM

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Other Key Findings

Any Predictive Factors for IAB Change? TI > SC Type 1 > Type 2 Factors such as race, age, country, baseline A1C

were NOT of predictive value for elevated IABs Prior exposure to insulin predicts slightly greater

IAB response in type 2 subjects on TI

Are the IAB changes reversible? IAB values trended towards baseline upon

TI discontinuation

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Any Clinical Significance?

HbA1c

FPG

Insulin dose

Hypoglycemia

Change in PFTs

Adverse events (including allergic events)

Discontinuations

R2 < 0.1 in All Cases

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Dissociation Between Change in IAB and A1C: Pooled Safety Population

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Conclusion

TI was observed to produce a greater insulin antibody response than sc insulins with no adverse clinical impact.

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Thank Thank YouYou

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Baseline Demographics and CharacteristicsSafety Population

Baseline Demographics and Characteristics

TI Comparator T Powder

(n=1795) (n=614) (n=1345) (n=599) (n=114)

Type 2 Type 1 Type 2 Type 1 Type 2

Gender, n (%)

Male 921 (51) 321 (52) 682 (51) 320 (53) 65 (57)

Female 874 (49) 293 (48) 663 (49) 279 (47) 49 (43)

Race, n (%)

Caucasian 1457 (81) 557 (91) 1080 (80) 547 (91) 91 (80)

Black 88 (5) 23 (4) 62 (5) 20 (3) 3 (3)

Hispanic 183 (10) 23 (4) 143 (11) 25 (4) 14 (12)

Asian 43 (2) 7 (1) 35 (3) 3 (1) 5 (4)

Other 24 (1) 4 (1) 25 (2) 4 (1) 1 (1)

Age (years), mean (±SD) 56.2 (8.7) 38.4 (12.6) 55.7 (8.8) 38.5 (12.5) 56.0 (9.8)

Weight (kg), mean (±SD) 88.1 (16.9) 76.7 (15.5) 87.8 (17.4) 76.8 (14.8) 90.0 (14.7)

BMI (kg/m2), mean (±SD) 31.1 (4.8) 26.1 (4.1) 31.0 (4.8) 26.0 (3.9) 30.9 (3.8)

Duration of Diabetes (years) 10.8 16.5 11.4 16.6 7.8