clinical development program

Clinical Development Program

Anne B. Cropp, Pharm.D.

Global Clinical Leader

2

Agenda

• Clinical Development Program Overview

• Clinical Pharmacology

• Efficacy

• Safety

3

Agenda



• Efficacy

• Safety

4


IND 43313 NDA EOP 2

Phase 2

Phase 3 Group I

1993 20051994 1995 1996 1997 1998 1999 20042003200220012000

Phase 1

102 103 104

1036 102 E 103 E 104 E

Phase 1 Studies Developmental

1001/1002

106 108 110

107 109 1009

111

1026 1027

1022 1029

1017

1028 1030

Phase 1 Studies Final Formulation

FDA Interactions Pre-NDA

Phase 3 Group II

Phase 3b

Exploratory

Efficacy

Long-term Safety

5

Clinical Development ProgramAdults – All Studies

Study Type INH SC Oral Agents

Total

Clinical Pharmacology StudiesNon-Diabetic SubjectsSubjects with DMSubtotal

676100776

473 97570

679100779

Controlled Phase 2/3 StudiesType 1 SubjectsType 2 SubjectsSubtotal

69812791977

705488

1193644644

140324113814

All Phase 2/3 StudiesType 1 SubjectsType 2 SubjectsSubtotal

91815802498

721496

1217648648

141324213834

All Studies 3274 1787 648 4613

6

Demographic Characteristics:INH-treated Adults in All Phase 2/3 Studies

Type 1N = 918

Type 2N = 1580

Gender N (%)MaleFemale

513 (55.9)405 (44.1)

991 (62.7)589 (37.3)

Age (Yr)MeanRange

38.118 – 65

56.623 – 80

Race N (%)WhiteHispanicBlackAsianOther

825 (89.8)48 (5.2)27 (2.9)7 (0.8)

11 (1.2)

1266 (80.1)127 (8.0)113 (7.2)29 (1.8)45 (2.9)

BMI (kg/m2)MeanRange

25.417 – 36

30.318 – 51

7

Duration of Exposure: INH-treated Adults in All Phase 2/3 Studies

Exposure Type 1N = 918

Type 2N = 1580

TotalN = 2498

> 0 months 918 1580 2498> 3 months 774 1463 2237> 6 months 684 1295 1979> 1 year 610 1088 1698> 2 years 304 517 821> 3 years 48 105 153> 7 Years 9 6 15Median Exposure (Subject-years) 1.74 1.72 1.73

Overall Exposure (Subject-years) 1491.1 2660.7 4151.8

8

Agenda



• Efficacy

• Safety

9

Clinical Pharmacology Studies Using the Phase 3 Formulation of INH

Study Type/Category Study Number Pharmacokinetics and Relative Bioavailability

Healthy Subjects 016, 017, 023, 1005, 1006, 1012, 1014, 1015, 1016, 1020

Subjects with type 1 DM 021, 018Subjects with type 2 DM 1003, 1004, 1007Special Populations Children/Adolescents with type 1 DM 018 Elderly, Obese Subjects with type 2 DM 1004 Gestational DM 1007 Nondiabetic Subjects with COPD 1005Smokers Nondiabetic 016, 1020

Type 2 DM 1003Japanese Subjects 023, 1016

Pharmacodynamics Healthy Subjects 017, 1016Subjects with DM 1003, 1004, 1007, 021, 1026

(Phase 3)

10

Clinical Pharmacology

• Bioavailability is approximately 10% relative to SC• Absorbed more rapidly than SC regular insulin and as

rapidly as SC insulin lispro• Dose-separated and dose-linear exposure over 1 to

6 mg• Three 1 mg blisters should not be substituted for one

3 mg blister• Age, gender, race, and BMI have no effects on PK • Smoking increases absorption rate and extent • Bioavailability higher in COPD, lower in asthma• Intra-subject variability of PK and PD comparable to

SC regular insulin in subjects with DM

11

Oral Inhalation of INH Bioavailability 10% Relative to SC Insulin

~30% retained in blister/device

~20% deposited in oropharynx

~10% tracheobronchial

~40% to alveolar spacesInsulin absorption siteEnzymatic degradation No preclinical or clinical evidence for accumulation

12







13

0

20

40

60

80

100

0 60 120 180 240 300 360 420 480 540 600

Mea

n G

luco

se I

nfus

ion

Rat

e (%

of M

axim

um)

Time (min)

INH 6 mgInsulin lispro 18 URegular insulin 18 U

INH Absorbed More Rapidly than SC Regular; as Rapidly as SC Lispro - Study 017

Diabetologia 2000;43(Suppl 1):A46.

14







15

Linear Increase in AUC with INH Dose

0

5000

10000

15000

20000

25000

30000

35000

0 1 2 3 4 5 6 7

Study 1012

2 x 3 mg

1 x 1 mg + 1 x 3 mg

3 mg2 x 1 mg

1 mg

Dose (mg)

AU

C 0-

600 (

µU.m

in/m

L)

Arithmetic meansIndividual AUC values

16

1

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

2

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

3

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

4

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

5

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

6

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

7

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000AU

C

8

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

9

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

10

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

11

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

12

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

14

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

15

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

16

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

17

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

18

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

113

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

120

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

201

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

402

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

1000

0 1 2 3 4 5 6 7DOSE

0

10000

20000

30000

40000

AUC

Individual AUC0-600 Study 1012

17







18

05

1015202530

0 100 200 300 400

3 X 1 mg 1 X 3 mg

Median Changes in Concentrations of Serum Insulin Over Time by Treatment

Med

ian

Con

cent

ratio

n (u

U/m

l)

Time (minutes)

Ratio AUC 140% (90% Cl 117-167%)

Ratio Cmax 127% (90% Cl 108-148%)3x1 mg1x3 mg

19







20







21

Agenda



• Efficacy

• Safety

22


IND 43313 NDA EOP 2

Phase 2

Phase 3 Group I

1993 20051994 1995 1996 1997 1998 1999 20042003200220012000

Phase 1

102 103 104

1036 102 E 103 E 104 E

1001/1002

106 108 110

107 109 1009

111

1022 1029


Phase 3 Group II

Phase 3b


1028 1030


1017

Exploratory

Efficacy

Long-term Safety

1026 1027

23


IND 43313 NDA EOP 2

Phase 2

Phase 3 Group I

1993 20051994 1995 1996 1997 1998 1999 20042003200220012000

Phase 1

102 103 104

1036 102 E 103 E 104 E

1001/1002

106 108 110

107 109 1009

111

1022 1029


Phase 3 Group II

Phase 3b


1026 1027

1028 1030


Type 1 DM Intensive 107

1022 1026

1027 Standard 102 106

1009

1017

Exploratory

Efficacy

Long-term Safety

24


IND 43313 NDA EOP 2

Phase 2

Phase 3 Group I

1993 20051994 1995 1996 1997 1998 1999 20042003200220012000

Phase 1

102 103 104

1036 102 E 103 E 104 E

1001/1002

106 108 110

107 109 1009

111

1022 1029


Phase 3 Group II

Phase 3b


1026 1027

1028 1030


1017

Exploratory

Efficacy

Long-term Safety

Type 2 DM Insulin Using

INH Rx Basal-bolus 103

108 1029

25


IND 43313 NDA EOP 2

Phase 2

Phase 3 Group I

1993 20051994 1995 1996 1997 1998 1999 20042003200220012000

Phase 1

102 103 104

1036 102 E 103 E 104 E

1001/1002

106 108 110

107 109 1009

111

1022 1029


Phase 3 Group II

Phase 3b


1026 1027


1017

1028 1030

Exploratory

Efficacy

Long-term Safety

Type 2 DM Oral Agents

INH Rx INH alone 109

110 INH + OA 104

109 1001/1002

26

Primary Endpoint: HbA1c Change from BaselineMean Treatment Group Differences, 95% CI

Adjusted Treatment Group Differences (INH-Comparator) in Change from Baseline in HbA1c(%)-3 -2.5 -2 -1.5 -1 -0.5 0 0.5 1

102

Type 1

Favors INH Favors Comp

27

Type 1

-3 -2.5 -2 -1.5 -1 -0.5 0 0.5 1

106 (18 years)

107 (18 years)

102


Adjusted Treatment Group Differences (INH-Comparator) in Change from Baseline in HbA1c(%)


28


Type 1

Type 2 Insulin Using


103

106 (18 years)

107 (18 years)

102


29


Type 1



108

106 (18 years)

107 (18 years)

103

102


30


Type 1


Type 2 Non-Insulin Using


104

106 (18 years)

107 (18 years)

103

102

108


31

-3 -2.5 -2 -1.5 -1 -0.5 0 0.5 1



104

106 (18 years)

107 (18 years)Type 1



103

102

108

109 (INH + OA vs. OA)

109 (INH vs. OA)

1001 High Stratum

110

1002 High Stratum


32

-3 -2.5 -2 -1.5 -1 -0.5 0 0.5 1



104

106 (18 years)

107 (18 years)Type 1



103

102

108

109 (INH + OA vs. OA)

109 (INH vs. OA)

1001 High Stratum

110

1002 High Stratum

1001 Low Stratum

1002 Low Stratum


33


IND 43313 NDA EOP 2

Phase 2

Phase 3 Group I

1993 20051994 1995 1996 1997 1998 1999 20042003200220012000

Phase 1

1036


1001/1002

106 108 110

107 109 1009

111

1026 1027

1017



Phase 3 Group II

Phase 3b

102 103 104

102 E 103 E 104 E

1022 1029

1028 1030

Exploratory

Efficacy

Long-term Safety

34

Efficacy Sustained Over 2 Years - Type 1 DMHbA1C Secondary Endpoint - Study 1022

INH N 276 261 249 238 234 230 221 209 288

SC N 280 274 266 260 253 237 230 219 286

INH-SC (95% CI): Month 12 0.27 (0.14, 0.40) Month 24 LOCF 0.25 (0.11, 0.39)

Mea

n H

bA1c

% (S

D)

Mea

n H

bA1c

% (S

D)

INHSC Insulin

55.5

66.5

77.5

88.5

99.510

0 3 6 9 12 15 18 21 24 27Baseline LOCFMonths

35

Efficacy Sustained Over 2 Years – Type 2 DM Insulin Using HbA1C Secondary Endpoint – Study 1029

INH N 296 279 269 259 249 244 235 224 314

SC N 292 288 281 263 253 240 238 231 303

INH-SC (95% CI): Month 12 0.08 (-0.06, 0.22) Month 24 LOCF 0.09 (-0.07, 0.25)

INHSC Insulin

Mea

n H

bA1c

% (S

D)

Months

55.5

66.5

77.5

88.5

99.510

0 3 6 9 12 15 18 21 24 27Baseline LOCF

36

5

6

7

8

9

10

11

12

0 3 6 9 12 15 18 21 24Months

INHOA and/or SC

INH N 156 156 157 155

OA N 143 142 141 141

Mea

n H

bA1c

% (S

D)

Baseline

Efficacy Sustained Over 2 Years – Type 2 DM Oral Agents HbA1C Secondary Endpoint – Study 1001/1002

37

INH N = 23 23 22SC N = 20 20 18

Prospective Pharmacodynamic Study in Type 1 DM Using Intensive Insulin Regimen - Study 1026

100

110

120

130

140

150

160

170

180 INHSC Insulin

Max

imum

Pos

tpra

ndia

l Glu

cose

C

once

ntra

tion

(mg/

dL) (

Mea

n +/

- SD

)

Baseline Week 12 Week 24

Mean HbA1c % (SD)

INH 6.79 (0.70) 6.63 (0.79) 6.73 (0.87)

SC 7.13 (0.56) 7.19 (0.85) 7.08 (0.95)

Heise T, Bott S, Tusek C, et al. The effect of insulin antibodies on the metabolic action of inhaled and subcutaneous insulin. Diabetes Care 2005;28:2161-9

38

-5 0 5 10 15 20 25 30

INH (N=102)SC (N=102)

BurdenConvenience

FlexibilityHassle

InterferencePain

Social

Standardized Treatment Satisfaction Scale ranges from 0 to 100.

Satisfaction Score: Mean Change (Baseline to Month 6)

Diabetes Treatment SatisfactionType 1 DM - Study 107, Intensive Insulin Regimen

Regimen

Outcomes

Net Benefit

Worsened Improved

Side EffectsEfficacy

AdvocacyPreference

General Satisfaction

39

Diabetes Treatment SatisfactionType 2 DM - Study 109

Worsened Improved

Satisfaction Score: Mean Change (Baseline to Month 6)Standardized Treatment Satisfaction Scale ranges from 0 to 100.

BurdenConvenience

FlexibilityHassle

InterferencePain

Social

Regimen

Outcomes

Net Benefit

-10 0 10 20 30 40 50

INH + OA (N=99)INH (N=100)OA (N=94)

Side EffectsEfficacy

AdvocacyPreference

General Satisfaction

40

Efficacy

• As effective as SC regular insulin in the treatment of patients with type 1 and insulin requiring type 2 DM

• Effective in type 2 DM used alone, in combination with basal insulin, and in combination with oral agent

• Sustained efficacy

• INH is patient - preferred therapy

41

Agenda



• Efficacy

• Safety

42

Safety

• Adverse Events, Serious Adverse Events, and Deaths

• Hypoglycemia

• Pulmonary Safety

• Insulin Antibodies

43

Adverse Events - All CausalityPatients with Type 1 DM - Controlled Phase 2/3 Studies

Number (%) Subjects

Preferred termINH

N=698SC

N=705Hypoglycemia 676 (96.8) 678 (96.2)Respiratory tract infection 297 (42.6) 292 (41.4)Cough increased 204 (29.2) 62 (8.8)Pharyngitis 126 (18.1) 112 (15.9)Tremor 125 (17.9) 129 (18.3)Flu syndrome 114 (16.3) 115 (16.3)Headache 109 (15.6) 113 (16.0)Rhinitis 100 (14.3) 72 (10.2)Accidental injury 85 (12.2) 83 (11.8)Asthenia 82 (11.7) 92 (13.0)Sinusitis 70 (10.0) 51 (7.2)Sweating 62 (8.9) 76 (10.8)

44

Adverse Events - All CausalityPatients with Type 2 DM - Controlled Phase 2/3 Studies

Number (%) Subjects

Preferred termINH

N=1279SC

N=488OA

N=644Hypoglycemia 792 (61.9) 364 (74.6) 185 (28.7)Respiratory tract infection 365 (28.5) 172 (35.2) 127 (19.7)Cough increased 275 (21.5) 41 (8.4) 24 (3.7)Tremor 221 (17.3) 96 (19.7) 58 (9.0)Flu syndrome 170 (13.3) 64 (13.1) 59 (9.2)Headache 168 (13.1) 36 (7.4) 67 (10.4)Asthenia 161 (12.6) 70 (14.3) 59 (9.2)Sweating 148 (11.6) 64 (13.1) 42 (6.5)Dizziness 142 (11.1) 66 (13.5) 38 (5.9)Back Pain 103 (8.1) 57 (11.7) 40 (6.2)Accidental injury 102 ( 8.0) 62 (12.7) 41 (6.4)Diarrhea 93 (7.3) 31 (6.4) 68 (10.6)

45

Serious Adverse Events – All Causality Controlled Phase 2/3 Studies

Patients with type 1 DM Number (events/1000 subject-months)Preferred Term INH N=698 SC N=705Hypoglycemia 25 (3.5) 36 (4.8)Loss of consciousness 8 (1.1) 12 (1.6)Myocardial infarction 3 (0.4) 3 (0.4)Diabetic ketoacidosis 3 (0.4) 1 (0.1)Convulsion 2 (0.3) 8 (1.1)Depression 0 5 (0.7)

Patients with type 2 DM INH N=1279 SC N=488 OA N=644Myocardial infarction 11 (0.8) 5 (0.8) 7 (1.1)Chest pain 7 (0.5) 1 (0.2) 4 (0.6)Angina 6 (0.4) 2 (0.3) 5 (0.8)Hypoglycemia 5 (0.4) 13 (2.1) 2 (0.3)Coronary artery disease 5 (0.4) 3 (0.5) 0Cellulitis 4 (0.3) 3 (0.5) 0Loss of consciousness 3 (0.2) 6 (1.0) 1 (0.2)

46

Deaths

32 Total Deaths

28 DeathsDuring or 30 days of Dose

4 Deaths>30 days of Dose

INH: 1Comparator: 3

*Incidence Rate: Deaths/1000 Subject-Months

Controlled Phase 2/3INH: 9/1977 (0.44*)

Comparator: 7/2012 (0.35*)

Uncontrolled Extensions

INH: 12/1449 (0.41*)Comparator: 0/45 (N/A*)

47

Safety


• Hypoglycemia



48

Hypoglycemic Events Controlled Phase 2/3 Studies

0

0.2

0.4

0.6

0.8

1

1.2

N=487 N=480 N=757 N=617

Even

ts/S

ubje

ct-M

onth

N=691 N=686

Type 1 Type 2Insulin Using

at Entry

Type 2Non-Insulin

Using at Entry

INHComparator

79.2% 77.7% 27.1% 25.6% 10.2% 3.1%

Proportion of Patients Reporting Hypoglycemia

49

02468

1012

0

0.5

1

1.5

2

2.5

HbA1C and Hypoglycemic Events in Studies Using Intensive Insulin Regimens - Studies 107, 1022, 1026, and 1027

Even

ts/S

ubje

ct-M

onth

Mean Baseline and End-of-Study HbA1c (%)

107

w, w/o= with, without subject 7988

1022 1026 1027 Even

ts/1

00 S

ubje

ct-M

onth

s

107 1022 IA1 1026 1027INH SC INH SC INH SC INH SC

N=103 N=103 N=288 N=286 N=23 N=19 N=95 N=101Baseline 7.8 7.8 7.4 7.5 6.8 7.1 7.6 7.6End-of Study 7.5 7.6 7.4 7.2 6.7 7.1 7.1 7.0

Protocol-defined SHE INHProtocol-defined SHE SC

FDA-defined HE INHFDA-defined HE SC

w/o

pooled 107 1022 1026 1027 pooled

w

50

Hypoglycemic Event Rates in Patients with Type 1 DM – Presented by Duration of Study Participation

INHSC InsulinControlled Phase 2/3 Studies

Even

ts/ S

ubje

ct-m

onth

Weeks since Randomization

0

0.5

1

1.5

2

2.5

0 4 8 12 16 20 24 28 32 36 40 44 48

INH N 685 672 658 613 602 581 265 256 254 249 245 242SC N 683 674 665 624 616 603 283 271 269 268 264 263

51

Hypoglycemic Event Rates in Adults with Type 1 DM – Onset Time of Day

0

0.05

0.1

0.15

0.2

0.25

0.3

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

Even

ts/S

ubje

ct-M

onth

Hour of Onset

Controlled Phase 2/3 Studies Patients with Type 1 DM Age 18 Years

INH N=691SC N=686

52

Safety


• Hypoglycemia



53

Pulmonary Safety

• Pulmonary Function Tests

• Chest X-ray and High Resolution Computerized Tomography (HRCT)

• Respiratory Adverse Events

54

Pulmonary Function Tests

• Measurements of Lung Function:– Spirometry

• FEV1, FVC, FEV1/FVC, PEFR, FEF25-75– Lung Volumes

• TLC, VC, RV, FRC, RV/TLC– Diffusing Capacity

• DLco, VA (alveolar volume), DL/VA

• Forced Expiratory Volume in 1 second (FEV1) – Standard spirometric endpoint sensitive to changes in airway function and lung

volume – Expressed in liters (L)

• Carbon Monoxide Diffusing Capacity (DLco) – Standard clinical test performed to assess the gas exchanging capacity of the

lung – Expressed in mL/min/mmHg

55

FEV1 Change from Baseline (L) Adjusted Mean Treatment Group Differences and 95% CI Type 1 and Type 2 DM - Phase 2 Studies 102, 103, 104

Adjusted Mean Change from Baseline in FEV1 (L)

102

103

104

Type 2

Type 1

-0.25 -0.15 -0.05 0.05 0.15 0.25

Favors Comparator Favors INH

56

FEV1 Change from Baseline (L) Adjusted Mean Treatment Group Differences and 95% CI for 3- and 6-Month Controlled PFT Phase 2/3 Studies

Adjusted Mean Change from Baseline in FEV1 (L)

102 106 (18 yrs) 107 (18 yrs)1026 1027103 108104109 (INH vs. OA)109 (INH + OA vs. OA)1101001 1002

Type 2

Type 1

-0.25 -0.15 -0.05 0.05 0.15 0.25

Favors Comparator Favors INH

57

0102030405060708090

100

<=-20 (-20,-15] (-15,-10] (-10,-5] (-5,0] (0,5] (5,10] (10,15] (15,20] >20

Perc

ent o

f Sub

ject

s (%

)

2 2 4 425

8

88 73

325283

177

215

2836

4 10 5 2 1 0

Range of Percent Change from Baseline in FEV1

Range of Percent Change from Baseline in FEV1 Type 1 DM - Controlled PFT Phase 2/3 Studies

3 Months INHComparator

58

Cha

nge

from

Bas

elin

e in

FEV

1 (L)

(M

ean

+/- S

D)

Visit (months)

-0.4-0.35

-0.3-0.25

-0.2-0.15

-0.1-0.05

00.05

0.10.15

Baseline 3 6 9 12 15 18 21 24 LOCF

INH 12-24 months: -0.041 L/yrSC 12-24 months: -0.041 L/yrINH - SC (90% CI): 0.000 (-0.022, 0.022)

INH N 277 260 247 240 235 226 217 208 282SC N 263 273 264 259 250 230 224 216 280

Change from Baseline in FEV1 – Patients with Type 1 DM - Study 1022

INH 3-24 months: -0.041 L/yrSC 3-24 months: -0.031 L/yrINH - SC (90% CI): -0.011 (-0.023, 0.002)

INHSC Insulin


59

Change from Baseline in FEV1 - Patients with Type 2 DM Insulin Using - Study 1029

INH 3-24 months: -0.058 L/yrSC 3-24 months: -0.058 L/yrINH-SC (90% CI): 0.000 (-0.016, 0.016)

INH N 292 278 266 257 246 237 230 218 303 SC N 290 281 276 265 251 235 233 224 301

Visit (months)

-0.4-0.35

-0.3-0.25

-0.2-0.15

-0.1-0.05

00.05

0.10.15

0 3 6 9 12 15 18 21 24 27Baseline LOCF

Cha

nge

from

Bas

elin

e in

FEV

1 (L)

(M

ean

+/- S

D)

INH 3-12 months: -0.057 L/yrSC 3-12 months: -0.079 L/yrINH - SC (90% CI): 0.022 (-0.010, 0.054)


INHSC Insulin

60

Change from Baseline in FEV1 – Patients with Type 2 DM Non-insulin Using - Studies 1001/1002

INH N 156 152 155 144 150 149 143Comparator N 141 130 143 127 134 134 125

Cha

nge

from

Bas

elin

e in

FEV

1 (L)

(M

ean

+/- S

D)

Visit (Months)

-0.5-0.45-0.4

-0.35-0.3

-0.25-0.2

-0.15-0.1

-0.050

0.050.1

0.150.2

0.250.3

Comparative

Baseline 6 9 12 15 18 21 24

INH 6-24 months: -0.075 L/yrComp 6-24 months: -0.075 L/yrINH-Comp (95% CI): 0.000 (-0.032, 0.033)

INH 6-12 months: -0.065 L/yrComp 6-12 months: -0.161 L/yrINH-Comp (95% CI): 0.096 (-0.013, 0.206)

INH 12-24 months: -0.087 L/yrComp 12-24 months: -0.066 L/yrINH-Comp (95% CI): -0.021 (-0.069, 0.026)

INHComparator

61

Comparative

12 weeks

Withdrawal

12 weeks

FEV1 Change Characterization – Onset and Resolution in Type 1 DM - Study 1027

RandomizationINH TID + Basal SC

SC BID-TID + Basal SC

62

-0.25

-0.2

-0.15

-0.1

-0.05

0

0.05

0.1

0.15


Comparative

Baseline

Visit (weeks)1 2 3 4 6 8 12

INH N 109 99 97 93 103 91 99 96SC N 116 99 102 97 100 101 103 97

Mea

n C

hang

e fr

om B

asel

ine

in

Prei

nsul

in F

EV1 (

L) (M

ean

+/- S

D)

INHSC Insulin

63


Comparative Withdrawal

Baseline

Visit (weeks)+41 2 3 4 6 8 12 +2 +8 +12

INH N 109 99 97 93 103 91 99 96 90 87 92 85SC N 116 99 102 97 100 101 103 97 92 96 92 93

Mea

n C

hang

e fr

om B

asel

ine

in

Prei

nsul

in F

EV1 (

L) (M

ean

+/- S

D)

-0.25

-0.2

-0.15

-0.1

-0.05

0

0.05

0.1

0.15

INHSC InsulinINHSC Insulin

64

Comparative


INHComparator

INH N 156 152 155 144 150 149 143Comparator N 141 130 143 127 134 134 125

Visit (Months)Baseline 6 9 12 15 18 21 24

-0.5-0.45

-0.4-0.35

-0.3-0.25

-0.2-0.15

-0.1-0.05

00.05

0.10.15

0.20.25

0.3

Cha

nge

from

Bas

elin

e in

FEV

1 (L)

(M

ean

+/- S

D)

65

-0.5-0.45

-0.4-0.35

-0.3-0.25

-0.2-0.15

-0.1-0.05

00.05

0.10.15

0.20.25

0.3

Comparative


INHComparator

INH N 156 152 155 144 150 149 143 139 123Comparator N 141 130 143 127 134 134 125 129 120

Withdrawal Phase

INHComparator

Visit (Months)Baseline 6 9 12 15 18 21 24 +6 +12

Visit (Weeks)

Cha

nge

from

Bas

elin

e in

FEV

1 (L)

(M

ean

+/- S

D)

66

INH

Withdrawal

6 months

SC insulin or OA

FEV1 Change Characterization – Withdrawal in Patients with Type 1 and Type 2 DM - Study 111

Studies 106, 107, 108, 109, 110, and

1009

Study 111

Uncontrolled Extension

3 months - 3 years

Controlled Phase 3

Group I Studies

3 - 6 month

67

FEV1 Change Characterization – Increases Following Withdrawal in Adult Patients with Type 1 and Type 2 DM - Study 111

Continued N = 115, 104 113 109

Discontinued N = 122, 118 119 116

Type 1 Type 2Continued INHDiscontinued INH

Cha

nge

from

Bas

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e in

FEV

1 (L)

M

ean

+/- S

D)

-0.4

-0.2

0

0.2

0.4

0 3 6Duration of Treatment (Months)1C

hang

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om B

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ine

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EV1 (

L)

Mea

n +/

- SD

)-0.4

-0.2

0

0.2

0.4

0 3 6Duration of Treatment (Months)1

Continued N = 198, 191 195 192

Discontinued N = 203, 201 199 197

Duration of Treatment (Months) Duration of Treatment (Months)

68

Pulmonary Function Tests – Summary

• INH-associated decreases in FEV1 – Occur early upon initiation of INH therapy– Are small in magnitude (approximately 1 to 1.5 %

of baseline) – Are not driven by outlier subjects with large changes– Are non-progressive with long-term INH

administration– Resolve upon discontinuation of INH

69

Pulmonary Safety




70

Chest X-ray Changes - Baseline to Last Observation Controlled Phase 2/3 Studies

Less AbnormalN = 2

More AbnormalN = 52

Change at Last Observation1:

INH54/1505 (3.6%)

SC15/909 (1.7%)

Oral Agent11/420 (2.6%)

1NDA cut-off, ongoing and completed studies

71

Follow-UpImaging:

25Resolved 22

On INH 18 Off INH 4

Lung CA 1 Thymoma 1 Mild Fibrosis 1

6Resolved 6

On INH 3 Off INH 3

6

Chest X-ray Changes - Baseline to Last Observation Controlled Phase 2/3 Studies

Localized to: Lung Parenchyma

29

Lung Vasculature

6

Extra-Pulmonary

6

Less AbnormalN = 2

More AbnormalN = 52

Abnormal at Last Observation:

INH54/1505 (3.6%)

SC15/909 (1.7%)

Oral Agent11/420 (2.6%)

Healed Fx 5Hiatal Hernia 1

LVH/ 9 CardiomegalyPacemaker 1Widened 1Mediastinum

MediastinalStructures

11

72

HRCT Results – 6-month Substudy in Patients with Type 1 and Type 2 DM

Controlled Phase 3 Studies 106, 107 (type 1 DM) and 108 (type 2 DM)

HRCT results INH(n = 53)

SC insulin (n = 63)

Normal at Baseline

Normal at End of Study (LOCF)

Yes Yes 43 (81.1) 49 (77.8)

Yes No 3 (5.7) 4 (6.3)

No Yes 0 2 (3.2)

No No 7 (13.2) 8 (12.7)

No Significant Change

5 (9.4) 6 (9.5)

More abnormal 1 (1.9) 2 (3.2)

Less abnormal 1 (1.9) 0

73

HRCT Results – 24-Month Substudy in Patients with Type 2 DM Insulin Using

Controlled Phase 3 Study 1029HRCT results INH

(n = 98)SC insulin

(n = 98)Normal at Baseline

Normal at End of Study

Yes Yes 62 (63.3) 62 (63.3)

Yes No 9 (9.2) 15 (15.3)

No Yes 8 (8.2) 7 (7.1)

No No 19 (19.4) 14 (14.3)

No Significant Change

19 (19.4) 10 (10.2)

More abnormal 0 2 (2.0)

Less abnormal 0 2 (2.0)

74

Pulmonary Safety




75

Respiratory Adverse Events - All CausalityType 1 and Type 2 DM - Controlled Phase 2/3 Studies

Preferred term

Number (%) of SubjectsType 1 DM Type 2 DM

INH N=698 SC N=705 INH N=1279 SC N=488 OA N=644All respiratory AEs 520 (74.5) 440 (62.4) 741 (57.9) 287 (58.8) 219 (34.0)Asthma 9 (1.3) 9 (1.3) 26 (2.0) 11 (2.3) 3 (0.5)Bronchitis 22 (3.2) 29 (4.1) 62 (4.8) 17 (3.5) 26 (4.0)Cough increased 204 (29.2) 62 (8.8) 275 (21.5) 41 (8.4) 24 (3.7)Dyspnea 31 (4.4) 6 (0.9) 44 (3.4) 9 (1.8) 9 (1.4)Edema pharynx 0 2 (0.3) 1 (0.1) 0 0Epistaxis 9 (1.3) 3 (0.4) 15 (1.2) 2 (0.4) 5 (0.8)Laryngitis 8 (1.1) 3 (0.4) 7 (0.5) 2 (0.4) 2 (0.3)Lung disorder 1 (0.1) 0 4 (0.3) 1 (0.2) 0Pharyngitis 126 (18.1) 112 (15.9) 119 (9.3) 44 (9.0) 38 (5.9)Pneumonia 6 (0.9) 8 (1.1) 11 (0.9) 7 (1.4) 4 (0.6)Respiratory disorder 51 (7.3) 29 (4.1) 70 (5.5) 45 (9.2) 11 (1.7)Respiratory tract infection 297 (42.6) 292 (41.4) 365 (28.5) 172 (35.2) 127 (19.7)Rhinitis 100 (14.3) 72 (10.2) 107 (8.4) 48 (9.8) 19 (3.0)Sinusitis 70 (10.0) 51 (7.2) 67 (5.2) 46 (9.4) 15 (2.3)Sputum increased 27 (3.9) 8 (1.1) 34 (2.7) 4 (0.8) 3 (0.5)Voice alteration 1 (0.1) 1 (0.1) 16 (1.3) 0 2 (0.3)

76

Cough in Controlled Phase 2/3 Studies

• Incidence and prevalence greatest during 1st month• Decreases with continued INH administration • Mainly mild in severity• 1% of INH-treated subjects discontinued due to cough• Cough assessment instrument was used in Phase 3

Studies 1022, 1027 and 1029 – Occurs within seconds to minutes after dosing – Occurs rarely at night– Rarely productive

• Not associated with decreases in FEV1

Preferred term


INH N=698

SC N=705

INHN=1279

SCN=488

OA N=644

Cough increased 204 (29.2) 62 (8.8) 275 (21.5) 41 (8.4) 24 (3.7)

77

Dyspnea in Controlled Phase 2/3 Studies

• Majority of cases mild in severity• Standardized dyspnea assessment instrument BDI/TDI

was used in Phase 3 Studies 1022, 1027 and 1029– No clinically important change with exposure of up to 2 years

• Five SAEs of dyspnea– 4 comparator– 1 INH

Preferred term


INH N=698

SC N=705

INHN=1279

SCN=488

OA N=644

Dyspnea 31 (4.4) 6 (0.9) 44 (3.4) 9 (1.8) 9 (1.4)

78

Serious Respiratory Adverse Events – All Causality Patients with Type 2 DM - Controlled Phase 2/3 Studies

Preferred term

INH(13,384 SME)

N (events/10,000 SME)

Comparator

(12,512 SME)N (events/10,000 SME)

Asthma 3 (2.24) 0Bronchospasm 1 (0.75) 0Cough 1 (0.75) 0Dyspnea 1 (0.75) 4 (3.20)Epistaxis 1 (0.75) 0Pneumothorax 1 (0.75) 1 (0.80)Respiratory distress 0 1 (0.80)Respiratory failure 1 (0.75) 1 (0.80)Vocal cord polyp 1 (0.75) 0

79

Asthma as an Adverse Event – All Causality Controlled Phase 2/3 Studies

Number (%) of Subjects with Asthma

Treatment Group Total Mild Moderate Severe Discontinued

Type 1 DM

INH N=698 9 (1.3) 3 5 1 2SC N=705 9(1.3) 7 2 0 0

Type 2 DMINH N=1279 26 (2.0) 13 11 2 7

SC N=488 11(2.3) 9 2 0 0OA N=644 3(0.5) 0 3 0 0

• There are more reports of severe asthma and asthma causing discontinuation in patients receiving INH treatment

• Asthma is reported infrequently and rarely causes discontinuation in patients receiving INH treatment

80

Pleural Effusion in Phase 2/3 Studies

• No cases in controlled 2-year studies• Eight INH-treated patients experienced pleural effusion

– 7 in Phase 2/3 Uncontrolled Extension Studies– 1 in COPD Study 1030

Study Age Gender Type Day of Onset Etiology111 13 yr male 1 Day 351 Idiopathic103E 60 yr male 2 Day 411 AIDS111 65 yr male 2 Day 524 Pulmonary edema111 58 yr male 2 Day 589 Post Cardiac Surgery111 64 yr male 2 Day 472 Surgical/iatrogenic – left

nephrectomy111 67 yr male 2 Day 562 Post Cardiac Surgery1036 58 yr male 2 Day 433 Unknown1030 72 yr male 2 Day 35 Pneumonia

81

Malignant Lung Neoplasm

Treatment groupNumber of

cases Cases per 10,000 SMEINH 3 0.94Comparator 1 0.80

Observed number of cases Expected number of cases*3 6.99 (95% CI: 5.23-8.98)

Observed vs. expected number of lung cancer cases among INH treated subjects.

*Ferrara A:The incidence of lung cancer, COPD, and Pneumonia, among persons with diabetes mellitus, Oakland, CA: Kaiser Permanente, 2004.

82

Intercurrent Respiratory Illness Glycemic Control and Hypoglycemic Events

Without Intercurrent Illness

With Intercurrent Illness

Patient Group INH Comparator INH Comparator

Mean Fasting Plasma Glucose (mg/dL)[N]Type 1 161.5 [170] 171.6 [159] 170.6 [177] 175.8 [164]

Type 2 insulin-using 138.1 [111] 151.5 [95] 136.5 [115] 144.4 [99]

Type 2 non-insulin-using 186.3 [98] 191.0 [65] 183.6 [102] 192.5 [70]

Hypoglycemic Event Rate (Events/Subject-Month)[N]

Type 1 0.969 [414] 0.950 [383] 1.049 [416] 1.294 [384]

Type 2 insulin-using 0.077 [260] 0.151 [232] 0.074 [261] 0.213 [234]

Type 2 non-insulin-using 0.112 [296] 0.101 [189] 0.142 [296] 0.047 [191]

83

Clinical Experience Among Patients with Mild/Moderate Asthma (INH vs Comparator with Asthma)

• Efficacy and Hypoglycemia–Equivalent changes in HbA1C–Similar hypoglycemia event rate

• Respiratory Adverse Events (AE) and Serious Adverse Events (SAE)–Similar number of patients with asthma AE– Increased INH patients with AEs of bronchitis, cough, dyspnea, pharyngitis, RTI and increased

sputum–1 Comparator with SAE of asthma exacerbation

• Study 1028: Asthma Exacerbations

• FEV1 changes– INH-associated treatment group differences similar in magnitude to those observed in patients

without asthma

Non-Severe SevereINH (N=72) Comp (N=67) INH (N=72) Comp (N=67)

Patients 30 26 11 9Events 203 155 15 10

84

Clinical Experience Among Patients with Mild/Moderate COPD (INH vs Comparator with COPD)

• Efficacy and Hypoglycemia–Equivalent changes in HbA1C–Decreased hypoglycemia event rate

• Respiratory Adverse Events (AE) and Serious Adverse Events (SAE)– Increased INH patients with AEs of bronchitis, cough, dyspnea, pharyngitis, respiratory disorder,

sinusitis and sputum increased–2 INH patients with SAE of COPD exacerbation (1 each), 1 INH patient with SAE of vocal cord polyp, 1

INH patient with SAE of epistaxis

• Study 1030: COPD Exacerbations

• FEV1 changes– INH-associated treatment group differences similar in magnitude to those observed in patients without

COPD

Non-Severe SevereINH (N=35) Comp (N=32) INH (N=35) Comp (N=32)

Patients 10 4 1 0Events 14 9 1 0

85

Safety


• Hypoglycemia



86

Insulin Antibodies

• INH associated increases in insulin antibodies were first observed in the Phase 3 Group I studies

• A semi-quantitative radioligand binding (RLB) assay was used to measure antibodies in these studies

• A quantitative RLB was developed and validated for use in the Phase 3 Group II studies

• Results using these assays have been used to extensively characterize and analyze INH-associated antibodies

87

Insulin Antibodies – Patients with Type 1 DM - Study 1022

88

Insulin Antibodies – Patients with Type 2 DM - Study 1029

89

Insulin Antibodies Following INH Withdrawal in Patients with Type 1 DM - Study 1027

90

Insulin Antibodies Following INH Withdrawal in Adult Patients with Type 1 DM - Study 111

N = 118 128 112 127 114 124 111 120

91

INH - Associated Insulin Antibodies (IAB) Methods to Examine Potential Clinical Impact

• Scatter plots – IAB levels and selected clinical parameters

• Binary distribution plots – IAB levels in subjects with and without selected clinical findings

• Time plots of FEV1 decreases and IAB levels

• Specific review of all adverse events of an allergic nature

92

Insulin Antibodies No Clinical Impact Identified

• No correlation of insulin antibody levels and – HbA1c

– Hypoglycemia– Insulin dose– PFTs

• IAB distributions no difference in subjects with– Cough– Dyspnea– Notable PFT declines

93

Change in HbA1c vs Change in Insulin Antibodies Type 1 - Study 1022 - 24 Months

Cha

nge

in H

bA1c

(%)

Change in IAB (U/ml)Excluding 4 INH patients

Inhaled Insulin (N=252)

-4

-3

-2

-1

0

1

2

3

4

-50 100 250 400 550 700 850 1000 1150 1300 1450

94

Potential Allergic Adverse Events

• Overall incidence of specific all-causality adverse events of an allergic nature was comparable among treatment groups in the Controlled Phase 2/3 studies

• One INH patient with type 2 diabetes experienced an apparent hypersensitivity reaction characterized by bronchospasm 1 month following initiation of INH therapy

– Peak serum antibody level of 632 µU/ml 2 months after initiating INH therapy

– 35% eosinophilia– Symptoms resolved promptly after discontinuation of INH and receipt of

standard treatment– No accompanying skin rash or angioedema

95

Cha

nge

from

Bas

elin

e in

Pre

Insu

lin

Dos

ing

FEV 1

(L)

Cha

nge

from

Bas

elin

e in

In

sulin

Ant

ibod

ies

(µU

/mL)

INH Withdrawal

Insulin Antibodies Do Not Correlate with Decreases in FEV1 – Study 1027

INH

SCINH Ins AB

Baseline1 4 6 8 12 +2 +82 3 +4

Comparative Withdrawal

+12

-0.3

-0.25

-0.2

-0.15

-0.1

-0.05

0

-50

0

50

100

150

200

250

300

350

Visit (weeks)

96

Insulin Antibodies Summary

• INH is associated with higher insulin antibody levels compared to SC insulin, more so in patients with type 1 than type 2 DM and women than men

• Mean antibody levels plateau after 6-12 months

• INH-associated insulin antibodies are of the IgG class, as are SC insulin-associated antibodies

• Insulin antibodies are not associated with changes in HbA1c, hypoglycemic event rates, insulin doses, or PFTs

• Insulin antibody levels decline after discontinuation of INH

97

Agenda

• Dr. Neville Jackson Introduction

• Dr. Anne Cropp Overview of Clinical Program

• Dr. William Cefalu Medical Need

• Dr. Neville Jackson Benefit and Managing the Risk

clinical development program

Documents

sc regular insulin

sc insulin lisprodose

uregular insulin

e phase

sc lispro study

extent bioavailability

doselinear exposure

pd comparable