The premixed insulin analogue

1
The premixed insulin analogue
Updated January 2006 Version 2006.1
2
Contents

• NovoMix 30 the premixed insulin
  analogue
• Formulation and proof of concept
• Benefits vs. other premixed insulins
• Premix analogue or glargine?
• Once-daily NovoMix 30
• The NovoMix 1-2-3 approach gets 77 to target
• Overall summary
• References

3
Formulation of premixes
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4
The dual-release insulin concept
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5
NovoMix 30 vs other premixed insulins

• Weyer C, et al Proof of concept study
• Pharmacodynamics following single-dose of
  NovoMix 30 and premixed human insulin in 24
  healthy volunteers
• Boehm B, et al
• 3-month study of twice-daily NovoMix 30 or
  premixed human insulin in 294 type 1 and type 2
  patients
• Schmoelzer I, et al
• Single-dose study of NovoMix 30 and premixed
  human insulin in 12 type 2 patients
• Warren ML, et al
• 4-week crossover study of pre- vs. post-meal
  administration of NovoMix 30 in 93 elderly type
  2 patients
• Hermansen K, et al
• Single-dose study of NovoMix 30, Humalog Mix
  25 and premixed human insulin in 45 type 2
  patients

6
Proof of conceptFaster onset of rapid-acting
part and similar duration of the basal component
compared with premixed human insulin
Weyer C, et al. Diabetes Care 19971016121614
7
Improved postprandial blood glucose compared with
human insulin after 3 months

Boehm B, et al. Diabet Med 200219393399
8
Prandial blood glucose increment 29 lower
compared with human insulin after 3 months
Boehm B, et al. Diabet Med 200219393399
9
Reduced major hypoglycaemia compared with human
insulin
Boehm B, et al. Eur J Int Med 200415496502
10
REACH Significantly fewer nocturnal glucose
readings below 3.5 mmol/l with NovoMix 30 than
human insulin
McNally P, et al. Diabetologia 200447(Suppl
1)A327
11
Reduced triglycerides with NovoMix 30 compared
with human insulin
Schmoelzer I et al. Exp Clin Endocrinol Diab
2005113176181
12
No difference in efficacy or safety between pre-
or post-meal dosing of NovoMix 30
Warren ML, et al. Diabetes Res Clin Pract
2004662329
13
Reduced glucose excursions vs. Humalog Mix25
and premixed human insulin30
p lt 0.001
17
p lt 0.05
n 61 type 2 diabetes patients
10
Mean injection dose 0.4 U/kg
Blood glucose excursion0 5 h (mmol/l/h)
Humalog Mix 25TM
NovoMix 30
Premixed human insulin
Hermansen K, et al. Diabetes Care 200225883888
14
Comparison with basal insulin

• Luzio S
• 24-h euglycaemic clamp study of equal total
  daily doses of NovoMix 30 BID and glargine OD in
  12 type 2 patients
• INITIATE, Raskin P
• 28-week study of NovoMix 30 BID or glargine OD
  in 233 type 2 patients with metformin /-
  pioglitazone with both insulins
• EUROMIX, Kann P
• 26-week study of NovoMix 30 BID metformin
  versus glargine OD glimepiride in 255 type 2
  patients

15
Insulin AUC 28 greater with NovoMix 30 compared
with equal daily dose of insulin glargine
Luzio S, et al. Diabetes 200453(Suppl. 2)A136
16
Glucose-lowering effect 34 greater with NovoMix
30 compared with equal daily dose of insulin
glargine
Luzio S, et al. Diabetes 200453(Suppl. 2)A136
17
Endogenous insulin suppressed 14 with NovoMix
30, but not with glargine
Luzio S, et al. Diabetes 200453(Suppl. 2)A136
18
INITIATE INITiation of Insulin to reach A1c
TargEt
Raskin P, et al. Diabetes Care 200528260265
19
INITIATETreat-to-target with forced titration
FBG or pre-dinner SMBG (mg/dl) (mmol/l) FBG or pre-dinner SMBG (mg/dl) (mmol/l) NovoMix 30 dose adjustment Glarginedose adjustment
lt 80 lt 4.4 ?2 U ?2 U
80?110 4.4?6.1 ? ?
111?140 6.2?7.8 2 U 2?4 U
141?180 7.83?10 4 U 4?6 U
gt 180 gt 10 6 U 6?8 U
Raskin P, et al. Diabetes Care 200528260265
20
INITIATE Similar baseline demographics between
treatment groups
NovoMix 30 Glargine
Patients treated 117 116
Age (years) 52.6 ? 10.6 52.3 ? 9.8
Gender () M/F 53/47 56/44
Ethnicity () C/B/H/A/O 55/15/27/2/2 52/17/26/4/1
Weight (kg) 90.6 ? 18.8 89.9 ? 19.0
BMI (kg/m2) 31.5 ? 5.5 31.4 ? 5.3
Prior TZD use () Y/N 32/68 33/67
Diabetes duration (years) 9.5 ? 5.9 8.9 ? 4.8
HbA1c () 9.7 ? 1.5 9.8 ? 1.4
Completed study 100 109
Discontinued due to adverse event 4 1

C Caucasian B Black H Hispanic A Asian O
other. Adverse event withdrawals in the
NovoMix 30 group were unrelated to treatment
stroke, adenocarcinoma, chest pain, and
gastrointestinal bleeding. One patient in the
glargine group withdrew because of injection site
stinging with possible relationship to study
drug.
Raskin P, et al. Diabetes Care 200528260265
21
INITIATE Improved blood glucose profiles with
NovoMix 30
Raskin P, et al. Diabetes Care 200528260265
22
INITIATE Improved postprandial glucose with
NovoMix 30
p lt 0.05 p lt 0.01
Difference in prandial glucose increment between
treatments (mmol/l)
NS
0.66
-0.59

-1.17
-1.25


Total mean prandial glucose increment
Breakfast Lunch Dinner
Raskin P, et al. Diabetes Care 200528260265
23
INITIATE Superior HbA1c and comparable FPG with
NovoMix 30 vs. glargine
Greater reduction in HbA1c
Comparable reduction in FPG
Raskin P, et al. Diabetes Care 200528260265
24
INITIATE More patients met HbA1c targets with
NovoMix 30 than glargine
Raskin P, et al. Diabetes Care 200528260265
25
INITIATE Hypoglycaemia

• One major hypoglycaemic episode reported during
  the trial this was in the glargine group
• At least one episode of minor hypoglycaemia (BG
  lt 56 mg/dl or 3.1 mmol/l) was experienced in 43
  of NovoMix 30-treated patients and 16 of
  glargine-treated patients
• Similar treatment satisfaction

Raskin P, et al. Diabetes Care 200528260265
26
INITIATE Weight gain, insulin dose and treatment
satisfaction

• End of trial parameters NovoMix 30 Glargine
• Total daily insulin dose (U/kg) 0.82 ?
  0.40 0.55 ? 0.27
• Split of NovoMix 30 dose between meals 4951
• Weight gain (kg) 5.4 ? 4.8 3.5 ? 4.5
• Weight gain per insulin unit (kg/U) 0.08 ?
  0.09 0.08 ? 0.09
• Treatment satisfaction (ITSQ) 51.0 ? 24.3 50.0
  ? 24.2
• (scale 25175, most positive to most negative)

(p 0.0013)
Raskin P, et al. Diabetes Care 200528260265
27
EuroMix Trial design
Kann et al. Endocrine Abstracts 200510OC8
28
EuroMix Patient characteristics
No. of patients (n, ITT population) NovoMix 30 /metformin (128) Glargine/glimepiride (127)
Age 61.5 9.3 61.0 8.9
Gender ( male) 53 49
BMI (kg/m2) 29.9 4.9 30.6 4.4
Time since diagnosis (years) 10.3 7.5 10.2 6.7
HbA1c () 9.2 1.4 8.9 1.3
All values are mean SD unless stated otherwise
Kann et al. Endocrine Abstracts 200510OC8
29
EuroMix Greater reduction in HbA1c with NovoMix
30/metformin than Glargine/glimepiride
D
Kann et al. Endocrine Abstracts 200510OC8
30
EuroMix Improved postprandial blood glucose with
NovoMix 30 vs. glargine
Values significantly lower for NovoMix
30/metformin than Glargarine/glimepiride, p lt 0.05
Kann et al. Endocrine Abstracts 200510OC8
31
EuroMix Mean prandial plasma glucose increment
Kann et al. Endocrine Abstracts 200510OC8
32
EuroMix Overall hypoglycaemia
NovoMix 30/metformin(n 123) Glargine/glimepiride (n 122)
Major Patients () Events (n) 0.8 1 0.8 1
Minor Patients () Events (n) Rate (events/pt./y) 20 67 1.5 9 20 0.4
Symptomatic Patients () Events (n) 10 34 6 17
Kann et al. Endocrine Abstracts 200510OC8
33
EuroMix Weight change
Significant change from baseline (95 CI
0.81 2.2)
Kann et al. Endocrine Abstracts 200510OC8
34
End of trial treatment doses
Treatment Daily dose Median Mean (U or mg) (U/kg)
NovoMix 30 25 U Last 0.19 EOT 0.40
Glargine 28 U Last 0.37 EOT 0.39
Metformin 2000 mg
Glimepiride 4 mg
Last last observation before leaving trial EOT
end of trial
Kann et al. Endocrine Abstracts 200510OC8
35
Once-daily NovoMix 30 lowers blood glucose over
24 hours

• Once-daily phase of the 1-2-3 Study

14
12
10
Blood Glucose (mmol/l)
8
6
4
Before
Before
After
Bedtime
Before
After
After
3am
Lunch
Breakfast
Dinner
36
Once-daily NovoMix 30 effective in lowering
HbA1c in type 2 diabetes
Suwanwalaikorn Diabetologia 200448(suppl
1)A308. Lund et al Diabetes 200556(suppl
1)A126. Kilo et al J Diabetes Complications
200317(6)307-13. Garber et al Diab Obes Metab
2005, in press
37
The 1-2-3 study Investigating NovoMix 30 OD,
BID and TID
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The 1-2-3 study Investigating NovoMix 30 OD,
BID and TID
If HbA1cgt 6.5, go to BID,d/c secretagogues
Phase 2
Pre-breakfast dinner x 16 week Add 3 U at
breakfast and titrate
End of Study
BID
HbA1c 6.5
Garber A, et al. Diabetes, Obesity and Metabolism
20068(1)58-66
39
The 1-2-3 study Baseline demographics
Number enrolled 100
Mean age SD (years) 56.7 11.5
Gender () M/F 50/50
Ethnicity () B-C-H-O 12-73-13-2
Mean weight SD (kg) 98.5 21.4
Mean BMI SD (kg/m2) 34.2 6.7
Prior OAD use () -OAD only OAD NPH OAD glargine 72 10 18
Mean diabetes duration SD (years) 11.1 7.1
Mean HbA1c SD () 8.6 0.8
B, black C, Caucasian H, Hispanic O, other
Garber A, et al. Diabetes, Obesity and Metabolism
20068(1)58-66
40
The 1-2-3 study Patient disposition

• 100 patients entered
• 74 patients completed
• 26 patients withdrew 12 achieved HbA1c lt 7
• Reason for withdrawal ineffective therapy (1),
  adverse events (5), non-compliance (7), other
  (13)
• No patients withdrew because of hypoglycaemia or
  weight gain

Garber A, et al. Diabetes, Obesity and Metabolism
20068(1)58-66
41

The 1-2-3 study Cumulative proportion of
patients achieving targets
HbA1c 6.5 (AACE, IDF goal) HbA1c lt 7(ADA goal)
OD 21 41
BID 52 70
TID 60 77
Baseline HbA1c was 8.6
Garber A, et al. Diabetes, Obesity and Metabolism
20068(1)58-66
42
The 1-2-3 study 2 reduction in HbA1c with OD,
BID or TID NovoMix 30
10
8.6
8
6.6
6
HbA1c ()
4
2
0
Baseline
OD, BID, TID
Garber A, et al. Diabetes, Obesity and Metabolism
20068(1)58-66
43
The 1-2-3 study Effect of NovoMix 30 on FPG
12
p lt 0.001
9.7
10
8
6.9
FPG (mmol/l)
6
4
2
0
Baseline
OD, BID, TID
Garber A, et al. Diabetes, Obesity and Metabolism
20068(1)58-66
44
Once-daily NovoMix 30 lowers blood glucose over
24 hours

• Once-daily phase of the 1-2-3 Study

14
12
10
Blood Glucose (mmol/l)
8
6
4
Before
Before
After
Bedtime
Before
After
After
3am
Lunch
Breakfast
Dinner
Garber A, et al. Diabetes, Obesity and Metabolism
20068(1)58-66
45
The 1-2-3 study Similar low hypoglycaemia rate
between phases
  Phase 1OD Phase 2 BID Phase 3 TID
Number of patients with major hypoglycaemic events 3 3 1
Rate of minor hypoglycaemic episodes 15 22 12
Major nocturnal hypoglycaemia episodes 0 0 0
Stepwise regression showed that there was no
correlation of hypoglycaemia with number of
injections

Garber A, et al. Diabetes, Obesity and Metabolism
20068(1)58-66
46
The 1-2-3 study Improved lipid profile and blood
pressure

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Parameter (baseline value)


9.0
10
HDL (45 mg/dl)
4.9
4.9
5
LDL (97 mg/dl)
0.7
Triglycerides (258 mg/dl)
0
Total Chol (188 mg/dl)
-5
-3.0
Mean change from baseline ()
-3.1
-4.8
Systolic BP (133 mmHg)


-10
?
Diastolic BP (79 mmHg)
-15
Weight (99 kg)
BMI (34 kg/m2)
-20
-19.9
p lt 0.001 ? p 0.003 p lt 0.02

-25
Garber A, et al. Diabetes, Obesity and Metabolism
20068(1)58-66
47
The 1-2-3 study Average insulin dose of NovoMix
30 by phase of study
Breakfast Breakfast Lunch Dinner
OD 0.60
BID 0.51 0.64
TID 0.58 0.25 0.25 0.70
Mean dose (U/kg) for subjects reaching HbA1c lt
6,5
Garber A, et al. Diabetes, Obesity and Metabolism
20068(1)58-66
48
The 1-2-3 study Summary

• On NovoMix 30 OD, 41 of patients achieved HbA1c
  lt 7.0
• On OD/BID/TID, 77 of patients achieved HbA1c lt
  7.0 and 60 achieved 6.5
• On OD/BID/TID, FPG levels were reduced from 173
  mg/dl (9.7 mmol/l) at baseline to 125 mg/dl (6.9
  mmol/l)
• The addition of a second or third injection of
  NovoMix 30 provides additional benefit in terms
  of FPG, PPG and HbA1c reductions, with no
  increased risk of hypoglycaemia
• Lipid profile and blood pressure significantly
  improved. This might reduce the cardiovascular
  risk

Garber A, et al. Diabetes, Obesity and Metabolism
20068(1)58-66
49
Overall summary of clinical studies
Back to contents

• NovoMix 30 vs. premixed human insulin 30/70
• improves postprandial blood glucose (Boehm et al
  2002)
• reduces risk of hypoglycaemia (Boehm et al 2004,
  McNally et al)
• dosing immediately before or after meal (Warren
  et al)
• reduces triglycerides (Schmoelzer et al)
• NovoMix 30 BID vs. glargine OD
• 34 higher glucose lowering effect in equal daily
  dose clamp (Luzio et al)
• 50 more patients reach HbA1c targets (Raskin et
  al)
• reduces PPG (Raskin et al)
• comparable FPG reduction (Raskin et al)
• equal risk of major hypoglycaemia and more minor
  hypoglycaemia (Kann et al)
• NovoMix 30 1-2-3 approach
• NovoMix 30 can be initiated OD and intensified
  to BID or TID. This approach brought 77 of
  patients below HbA1c of 7.0 in The 1-2-3 study
  (Garber et al)

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References

• Boehm B, et al. Diabet Med 200219393399
• Boehm B, et al. Eur J Int Med 200415496502
• Garber A, et al. Diab Obes Metab 2005 in press
• Hermansen K, et al. Diabetes Care 200225883888
• Kann P, et al. Endocrine Abstracts 200510OC8
• Luzio S, et al. Diabetes 200453(Suppl. 2)A136
• McNally P, et al. Diabetologia 200447(Suppl
  1)A327
• Raskin P, et al. Diabetes Care 200528260265
• Schmoelzer I, et al. Exp Clin Endocrinol Diab
  2005113176181
• Warren ML, et al. Diabetes Res Clin Pract
  2004662329
• Weyer C, et al. Diabetes Care 19971016121614