Biodel - ATTD - Basel 12feb 10

February 2010
Physiologic Insulin PK and Replacement

First Phase insulin release covers
Basal insulin covers glucose from liver glucose from GI tract and signals liver
(hepatic glucogenesis) to cease production of glucose
Long acting insulin effort: glargine,
glargine (hepatic glucogenesis)
detemir Rapid acting insulin effort: aspart,
lispro and glulisine
120
Blood Gluc
100
ma Insulin
U/ml)
80
-140
(U
cose (mg/dl)
Plasm
60
-80
40
20
0
Meal Meal Meal

Time
3rd International Conference on Biodel Inc. 2010
ADVANCED TECHNOLOGIES & www.biodel.com
TREATMENTS FOR DIABETES 1
Rapid Secretion Of Insulin After Meals In Normal
Non-diabetic Humans Wolever et al: J. Nutr.126: 2807-2812, 1996.
In normal humans, after

a mixed meal, insulin peaks
30 45 minutes
30-45 i
after the meal.
Insulin reaches half of max
concentration at
~ 16-18 minutes
Different types of mixed meals

Rapid-Acting Insulins Have Essentially the
Same Profile
Personal Communication from Prof

Prof. Lutz Heinemann

Post-prandial hyperglycemia is far too high even in
well controlled patients
Post-Prandial Excursions
160
141 Well-controlled T1DM: n=7 meals
140
68 H
Hybrid
b id closed
l d loop
l T1DM:
T1DM n=14
14 meals
l
prandial - Baseline
120
27 Older normal, no DM: n=3 meals
100 16 Young normal, no DM: n=9 meals
Glucose e
80
(mg/dl))
60
40
Post p
20
-20
20
0 20 40 60 80 100 120 140 160 180 200
Time after meal (min)

2-Hour Plasma Glucose and Cardiovascular Mortality
>198
mg/dl
<140
mg/dl
<110
110 mg/dl
/dl <139 mg/dl

How Fast is SC absorption of Different
Insulin Preparations?
Mean Times to reach half-maximal insulin levels (single bolus given by subcutaneous injection)
Regular 55 min Lilly, Inc

40-50 min
g
Regular 37 min Heinemann
Aspart 23 min Lindholm

Aspart 35 min Holmes 2008
Holmes,
25-30 min
Lispro 26 min Heinemann
Lispro 25 min Lilly, Inc
j
VIAject 13 min Heinemann, others
8-13 min
VIAject 8 min Data on file, Biodel
Holmes et al: Br J Clin Pharmacol 2008; 60:5 469476

Li dh l et al:l Clin
Lindholm Cli Pharmacokinet
Ph ki 2001 40 (9)
2001; (9): 641
641-659
659

VIAject Technology
EDTA
Hexameric Insulin - Charged
+ -
I
I+ -
+ I I
-
I I 2 Zn 2+
I I+
I I -
I- +
- + I
Monomeric Insulin - Neutral Charge

Phase 1
Pharmacokinetic Profile
100
90
80
70 12 IU VIAject
max
% Insulin Cm
60
12U Lispro
50 12 IU RHI
40
30
20
10
0
0 10 20 30 40 50 60 70 80 90 100 110 120
Time (min)

Phase 1
Pharmacodynamic Profile
12 12 IU RHI
min.
12 U Lispro
Baseline corr. GIR mg/kg/m
10
12 IU VIAject
8
0
0 1 2 3 4 5 6 7 8
Hours

Meal Study in Pts. with Type 1 Diabetes
Pharmacokinetics
Early 1/2 Tmax (min) Ins Tmax (min) Late 1/2 Tmax (min)
50 200 350
45 180
300
40 160
35 140 250
30 120 200
25 100
20 80 150
15 60 100
10 40
50
5 20
0 0 0
RHI Li
Lispro Vi j
Viaject RHI Li
Lispro Vi j t
Viaject RHI Li
Lispro Vi j t
Viaject
PK-Parameters RHI Lispro VIAject p-value

a < 0.001 RHI vs. VIA
Early Tmax (min) 38.4+19.5 a, c 25.4+7.6 b,
b c 13.15.2 a, b b 0.001 LIS vs. VIA
c < 0.001 RHI vs. LIS
Ins Tmax (min) a, c 65.634.5 b, c 28.417.4 a, b
131.749.5 b 0.001 LIS vs. VIA
Late Tmax (min) a, c 147.551.7 b, c 135.245.7 a, b
268.354.3 b 0.391 LIS vs. VIA

Phase 2 Meal Study Mean Curves
Improved Postprandial Glycemic Control
18 Patients Average Blood Glucose
200
190
180
RHI
ose (mg/dL)
170
160
150 Lispro
140
Blood Gluco
130
120 VIAject
110
100
B
90 Meal
80
70
60
-30 0 30 60 90 120 150 180 210 240 270 300 330 360
Time (min)
Interim analysis RHI Lispro VIAject

Post prandial Glucose Max-Min (0 to 180 Minutes)
100
90
RHI Lispro VIAject
90.6 89.2
se Min (0-180 minutess)
Max Blood
80
70
69.8
60
d Glucose M
50
40
30
Glucos
Blood
20
10
RHI vs. VIAject p=0.007

Lispro vs. VIAject p=0.011
p p
RHI vs. Lispro p=0.858

Hypoglycemia-Prevention:
Glucose Infused 180- 480 Minutes
200
RHI Lispro VIAject
d
ucose Infused
150
0 Minutes
126.9
Amount of Glu
180-480
100
A
50
45.1
27.1
0
RHI vs. VIAject p=0.012

Lispro vs. VIAject p=0.642
p p
RHI vs. Lispro p=0.039

Robust Phase 3 Study Design

vs. Humulin R (per FDA EOP2)
Two open label studies

Type 1 patients
Type 2 patients
6 month duration
Non-inferiority HbA1c
Hypoglycemia
Weight
Safety

HbA1c Patients with Type 1 Diabetes (06J)
10
9.5 Viaject RHI
8.5
%)
HbA1c (%
7.91 + 0.116
8
7.52 + 0.102
7.82 + 0.107 7.60 + 0.112
7.5 7.53 + 0.105
7 59 + 0.101
7.59 0 101
7
6.5
6
Baseline Week 12 Week 26
Completer population (US and Germany)

Germany).

HbA1c Patients with Type 2 Diabetes (08J)
10
9.5
Vi j
Viaject RHI
9
c (%)
8.5
8 18 + 0.068
8.18 0 068
HbA1c
8 7.67 + 0.096
8.13 + 0.106
7.55 + 0.085
7.5
7 43 + 0.074
7.43 0 074
7.49 + 0.068
7
6.5
6
Baseline Week 12 Week 26
Completer population.
population

Type 1 Pt. Weight Change at 6 Months
15
1.5 1 64
1.64
ange (kg)
= 1.91
1 91 kkg
Weight Cha
05
0.5
p<0.0001
0
-0.26
-0.5
-1
VIAject RHI
Completer population (US and Germany)

Germany).

Type 2 Pt. Weight Change at 6 Months
1.5
1.54
ange (kg)
= 0.86 kg
Weight Cha
1 p<0.03
0.68
0.5
0
VIAject RHI
Completer population.
population

Type 1 Pts. - Severe Hypoglycemic Events
Number of subjects with at least one SHE

((% with at least one event))
Treatment
Day 1-42 Day 43-84 Day 85-126 Day 127-End Overall
Group
VIAject 4 (2.2) 2 (1.4) 2 (1.5) 2 (1.6) 8 (4.4%)
RHI 6 (3.4) 6 (3.9) 4 (2.8) 1 (0.6) 15 (8.6%)
47% reduction in number of subjects with

severe hypoglycemic events
ITT p
population
p (US
( and Germany).
y)

Type 2 Pts. Mild to Moderate Hypoglycemic Events
ITT Completers
[# of events/ rate [# of events/ rate
(incidents/month)] (incidents/month)]
VJ 1919 / 1.6 VJ 1785 / 1.7
RHI 3144 / 2
2.4
4 RHI 3072 / 2
2.5
5
p=0.003 p=0.051
VIAject % Reduction Rate = 39% (ITT)

Phase 3 Results March 2009 Conclusions
Completed both Type 1 and Type 2 studies July 2008
Type 1
+ Numeric reduction in severe hypoglycemia
+ Less weight gain
- Pain on injection with 25 IU/ml pH4 formulation
Since replaced by more tolerable 100 IU /ml pH7 formulation
= HbA1c control achieved non inferiority after exclusion of anomalous data from India
Type 2
+ Reduction in mild to moderate hypoglycemia
+ Less weight gain
- Pain on injection
j with 25 IU/ml pH4
p formulation
Since replaced by more tolerable 100 IU /ml pH7 formulation
= HbA1c control achieved non inferiority

Successfully Bridged from 25 IU pH 4
to 100 IU pH 7 Mitigating Tolerability Concern
Reduced volume and acidity = improved tolerability
Successfully met primary endpoint

Area under the serum insulin concentration curve for the time interval
0-480 min (AUCINS0-480) and
Maximum serum insulin concentration post-dosing (CINS max)

2009 VIAject NDA
NDA Submission December 2009
Anticipated PDUFA date October 30, 2010

Pre-NDA meeting with FDA confirmed strategy of submission with
existing data
Bridged to more convenient, tolerable and stable 100 IU pH 7 liquid
formulation
Disposable pen finalized NDA to be supplemented
NDA includes:
10 mL vial
3 mL pen cartridge
Re-usable pen referenced in NDA

VIAject-015J
Effect of prandial treatment with VIAject

compared to regular human insulin and
insulin lispro on postprandial endothelial
function and microvascular stress in type 2
diabetic patients

Microvascular Blood Flow during OGT in Non-
Diabetic Subjects
250
37C
37 C
44C
200
Inccrease LDF (%)
150
100
50
0
15 30 60 90 120
minutes
Forst et al., Exp Clin Endokrionol Diab, 1998

Postprandial Myocardial Microvascular Blood Flow
15
Control
al Flow
T2DM
p<0.01
10
Myocardia
5
M
p<0.01
0
Baseline Postprandial
Scognamiglio R.
R et al.,
al Circulation,
Circulation 2005,
2005 112: 179
179-184
184

Endothelial Function and Microvascular Stress
Following Prandial Administration Type 2 Patients
Asymmetric Dimethylarginine (ADMA)
Peak Postprandial Change from Baseline
140 97.7 24.4 *
RHI
120
66.9 33.9 *
Lispro
mol/L)
100
80 VIAject
ADMA (nm
60
40
20
0
-20 *: p< 0.05 vs. VIAject
40
-40
-60 -27.3 22.6
Asymmetric Dimethylarginine: A biochemical marker of oxidative stress

Nitrotyrosine postprandial change from baseline
0.5
0.25 0.15 *
04
0.4 RHI
0.3 Lispro
mol/L)
0.09 0.07
0.2 VIAject
ADMA (nm
0.1
-0.1
-0.2
-0.3 *: p< 0.05 vs. VIAject

04
-0.4
-0.5 -0.26 0.17

Blood Flow change from baseline 0-120 min
15
Lispro
RHI
10 VIAject
*
5
w [AU]
LDF shallow
-5
L
-10
-15
15
0 30 60 90 120
*p<0.05 vs. RHI

p<0.05 vs. Lispro

O2 Saturation change from baseline
10
Lispro
RHI
* VIAject
ject
*
5
shallow SO2 [% AU]
0
s
-5
-10
10
0 30 60 90 120 150 180 210 240
*p<0.05 vs. RHI

p<0.05 vs. Lispro

Conclusion
The ultra-rapid
ultra rapid absorption of VIAject insulin
reduces postprandial oxidative stress and
improves
p vascular function after a test meal
more effectively than regular human insulin and
the fast acting analogue insulin lispro.
These findings were independent from glycemic
control.

Summary of Clinical Experience with VIAject
Human Insulin Formulation with Unique Mechanism of Absorption
More Rapid Absorption than RHI and Rapid Acting Analogs
Less Weight Gain than RHI in Both Type 1& 2 Pts.
Less Severe Hypoglycemia in Type 1 Pts. than RHI
Less Non-Severe Hypoglycemia in Type 2 Pts.
Equivalent Control of HbA1c to RHI
Better Post-prandial
Better Post prandial Glycemic control in Type 1 Pts
Pts.
Normalization at meal time of Markers of Oxidative Stress, Blood Flow &
Oxygen Saturation in Type 2 Pts
Pts.


Thank you
P
Presentations
t ti available
il bl at:
t www.biodel.com
bi d l
News and Events
Presentations and Publications


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February 2010

Physiologic Insulin PK and Replacement

Meal Meal Meal

In normal humans, after

Different types of mixed meals

3rd International Conference on Biodel Inc. 2010

Personal Communication from Prof

3rd International Conference on Biodel Inc. 2010

3rd International Conference on Biodel Inc. 2010

3rd International Conference on Biodel Inc. 2010

Regular 55 min Lilly, Inc

Aspart 23 min Lindholm

Holmes et al: Br J Clin Pharmacol 2008; 60:5 469476

3rd International Conference on Biodel Inc. 2010

Monomeric Insulin - Neutral Charge

3rd International Conference on Biodel Inc. 2010

3rd International Conference on Biodel Inc. 2010

PK-Parameters RHI Lispro VIAject p-value

3rd International Conference on Biodel Inc. 2010

Interim analysis RHI Lispro VIAject

3rd International Conference on Biodel Inc. 2010

RHI vs. VIAject p=0.007

3rd International Conference on Biodel Inc. 2010

RHI vs. VIAject p=0.012

3rd International Conference on Biodel Inc. 2010

Two open label studies

3rd International Conference on Biodel Inc. 2010

9.5 Viaject RHI

Completer population (US and Germany)

3rd International Conference on Biodel Inc. 2010

3rd International Conference on Biodel Inc. 2010

Completer population (US and Germany)

3rd International Conference on Biodel Inc. 2010

3rd International Conference on Biodel Inc. 2010

Number of subjects with at least one SHE

47% reduction in number of subjects with

3rd International Conference on Biodel Inc. 2010

VIAject % Reduction Rate = 39% (ITT)

3rd International Conference on Biodel Inc. 2010

3rd International Conference on Biodel Inc. 2010

Reduced volume and acidity = improved tolerability

Successfully met primary endpoint

3rd International Conference on Biodel Inc. 2010

Anticipated PDUFA date October 30, 2010

3rd International Conference on Biodel Inc. 2010

Effect of prandial treatment with VIAject

3rd International Conference on Biodel Inc. 2010

Forst et al., Exp Clin Endokrionol Diab, 1998

3rd International Conference on Biodel Inc. 2010

3rd International Conference on Biodel Inc. 2010

Asymmetric Dimethylarginine: A biochemical marker of oxidative stress

3rd International Conference on Biodel Inc. 2010

-0.3 *: p< 0.05 vs. VIAject

-0.5 -0.26 0.17

3rd International Conference on Biodel Inc. 2010

*p<0.05 vs. RHI

3rd International Conference on Biodel Inc. 2010

*p<0.05 vs. RHI

3rd International Conference on Biodel Inc. 2010

3rd International Conference on Biodel Inc. 2010

3rd International Conference on Biodel Inc. 2010

3rd International Conference on Biodel Inc. 2010

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