1. ©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 1 Insulin Antibodies Associated with Technosphere ® Insulin (TI) Wen Yu, Mark T. Marino, James P. Cassidy, Anders H. Boss, Samuel Fineberg

2. ©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 TrialsTIComparators Type 1614599 Type 217331398 All diabetes23471997 1. 1. What are the insulin antibody (IAB) changes? 2. 2. Clinical significance?

3. ©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 3 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.

4. ©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 < 6 as AFREZZA pH > 6 in the lungs

5. ©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 5 IABs: Brief Background Historical concern and clinical significance Many factors at play 1 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 consequences 2 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

6. ©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 6 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

7. ©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 7 What Are The IAB Changes? Study No./ Diabetes Typen Baseline (U/mL) Week 26 (U/mL) Week 52 (U/mL) 009 / Type 1 TI2837.2 (0.8, 531.1) 58.6 (0.8, 726.4) 48.2 (1.9, 933.2) sc insulin2606.6 (0.8, 200.0) 8.2 (0.8, 200.0) 8.7 (0.8, 192.4) 102 / Type 2 TI3006.1 (0.8, 138.6) 14.9 (0.8, 586.5) 14.5 (0.8, 532.5) sc insulin3095.6 (0.8, 141.3) 8.9 (0.8, 190.5) 8.7 (0.8, 197.3) Median Insulin Antibodies (Kronus ® Units/mL)

8. ©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 8 IAB Temporal Pattern Pooled Safety Population, Type 1 and Type 2 DM

9. ©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 9 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

10. ©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 10 Any Clinical Significance? HbA1c FPG Insulin dose Hypoglycemia Change in PFTs Adverse events (including allergic events) Discontinuations R 2 < 0.1 in All Cases

11. ©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 11 Dissociation Between Change in IAB and A1C: Pooled Safety Population

12. ©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 12 Conclusion TI was observed to produce a greater insulin antibody response than sc insulins with no adverse clinical impact.

13. ©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 13 Thank You

14. ©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 14 Baseline Demographics and Characteristics Safety Population Baseline Demographics and Characteristics TIComparatorT Powder (n=1795)(n=614)(n=1345)(n=599)(n=114) Type 2Type 1Type 2Type 1Type 2 Gender, n (%) Male921 (51)321 (52)682 (51)320 (53)65 (57) Female874 (49)293 (48)663 (49)279 (47)49 (43) Race, n (%) Caucasian1457 (81)557 (91)1080 (80)547 (91)91 (80) Black88 (5)23 (4)62 (5)20 (3)3 (3) Hispanic183 (10)23 (4)143 (11)25 (4)14 (12) Asian43 (2)7 (1)35 (3)3 (1)5 (4) Other24 (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/m 2 ), 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)10.816.511.416.67.8