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©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
©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?
©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.
©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
©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 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
©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”
©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 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)
©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 PatternPooled Safety Population, Type 1 and Type 2 DM
©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
©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
R2 < 0.1 in All Cases
©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
©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.
©2010 MannKind Corporation. All rights reserved. No copying or distribution of this material may be made without written consent of MannKind Corporation. 13
Thank Thank YouYou
©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 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