Toujeo Speaker Slide Deck TW - Tjo.16.04.03 FINAL

Advances in Diabetes Care:
Next Generation Basal insulin
TW.TJO.16.04.03
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Table of contents
Current unmet needs with insulin therapy
Clinical pharmacology of insulin glargine U300
EDITION Program
Summary
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Current Unmet Needs With Insulin

Therapy
What is the importance of insulin therapy?
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UKPDS: Decrease in HbA1c results in a reduction in the

relative risk of complications
*p < 0.0001 vs. baseline; #p = 0.035.
Lower extremity amputation or fatal peripheral vascular disease.

5
Stratton I, et al. BMJ 2000;321:405-12.
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UKPDS: Legacy effect of earlier intensive glucose control

After median 8.5 years post-trial follow-up
Aggregate Endpoint
1997
2007
Any diabetes-related endpoint
RRR:
p:
12%
0.029
9%
0.040
Microvascular disease
RRR:
p:
25%
0.0099
24%
0.001
Myocardial infarction
RRR:
p:
16%
0.052
15%
0.014
All-cause mortality
RRR:
p:
6%
0.44
13%
0.007
RRR = relative risk reduction, p = log rank

6
Holman RR wt al., N Engl J Med 2008;359:1577-89.

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Efficacy of basal insulin in T2D patients uncontrolled

with OAD was demonstrated in insulin glargine trials
6.9%
7.0%
1.2 kg
7.0%
1.8 kg
-1.8%
-1.7%
INITIATE1
APOLLO2
7.0%
1.8 kg
-1.6%
TTT3
7.1%
1.6 kg
-1.5%
INSIGHT4
Endpoint HbA1c
HbA1c change from baseline
weight per absolute 1% HbA1c
7.1%
7.1%
7.2%
2.6 kg
0.8 kg
-1.7%
LAPTOP5
1.3 kg
-1.5%
-2.0%
LANMET6 Rosenstock7
0.9 kg
-1.5%
L2T38
RCTs insulin glargine group:

mean daily dose 0.33-0.70 U/kg
Adapted from: 1. Yki-Jarvinen et al. Diabetes Care 2007;30:1364 2. Bretzel et al. Lancet 2008;371:1073 3. Riddle et al.
Diabetes Care 2003; 26:3080 4. Gerstein et al. Diabetic Medicine 2006;23:736 5. Janka et al. Diabetes Care
2005;28:254 6. Yki-Jarvinen et al. Diabetologia 2006;49:44251 7. Rosenstock et al. Diabetologia 2008;51:408 8.
Swinnen, et al. Diabetes Care 2010; 33:1176
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ADA-EASD position statement update:

Management of hyperglycemia in T2DM, 2015
Anti-hyperglycemic therapy
Glycemic targets
HbA1c < 7.0% (53.0 mmol/mol)
Overly aggressive control in older patients with
more advanced disease may not have significant
benefits and may indeed present some risk
Personalization is necessary
Avoidance of hypoglycemia
PG, plasma glucose.
Inzucchi SE, et al. Diabetes Care 2015;38:140-9.
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2015 ADA EASD position statement: Management of

hyperglycemia in T2D
Inzucchi SE, et al. Diabetes Care 2015;38:140-9.
ORIGIN: Insulin provides long-term near-normal

glycemic control
HbA1C, %
7.0
ORIGIN study
IGT, IFG or early T2DM at high
CV risk
N=12,537
Randomized to Gla-U100 (with a
target FPG 95 mg/dL [5.3 mmol/L])
vs standard care
Median follow-up of 6.2 years
6.5
6.5
6.4
6.4
6.3
6.4
6.2
6.2
6.0
6.0
6.5
6.3
6.2
6.1
6.0
5.9
5.5
6.5
6.4
Gla-U100
Standard care
2
Years
Gla-U100 had a neutral effect on the primary CV endpoints vs standard care

Rates of severe hypoglycemia were 1.00 (Gla-U100) vs 0.31 (standard) per
100 person-years
Median weight increased by 1.6 kg with Gla-U100 and fell by 0.5 kg with standard care
10
ORIGIN trial invest. New Engl J Med 2012;367:319-328.

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Insulin provides sustained HbA1C reduction

for over 5 years
In ORIGIN, 88% of participants had a prior diagnosis of diabetes (mean
duration 5.4 years) or newly detected diabetes
In a subanalysis of diabetes patients only, early intervention with Gla-U100 kept
median HbA1c near starting levels for 5 years
% of participants with HbA1C <6.5%
100
Gla-U100
90
Standard care
80
70
60
50
40
0
Years
Insulin Treatment has the long-term benefits

How about in the real world?
11

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Real World Study

Delayed basal insulin initiation despite elevated HbA1C
Mean (SD) pre-insulin duration of OAD ranged from 6.3 (5.1) years in China to
11.4 (7.5) years in Italy
Mean (SD) HbA1C of patients initiating insulin was 8.9 (1.6) %
Mean (SD) pre-insulin HbA1C was highest in the UK (9.8 [1.8] %) and lowest in
China (8.3 [1.7] %)
Proportion of patients with HbA1C 9.0%
70
SOLVE study
24-week
international
observational study
60
50
40
10 countries
30
N=17,374
20
T2DM on 1 OADs
10
0
Poland Germany China Spain Canada Portugal Italy
Israel
UK
Turkey
Total
12
SOLVE, Study of Once Daily Levemir

Khunti K et al. Diabetes Obes Metab. 2012;14:654-61
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Survey of Basal Insulin Use for T2D in Taiwan

Insulin adherence
registry (20102012)1
FINE-Asia
Taiwan (20062008)2
RIDA
(2005-2006)3
836
417
694 (only
basal)
F/U duration
24 weeks
(prospective)
6 months
(prospective)
12 months
(retrospective)
Mean age (year)
62.2
60.1
61.1
Mean diabetes duration

(year)
11.6
11.5
9.7
Mean body weight (kg)
66.3
65.5
66.1
Mean baseline A1C (%)
10.1
10.2
10.0
Mean A1C (%)
-1.4
-1.3
-1.2
Patients with A1C < 7% (%)
10.7
10.6
11.2
Mean baseline FPG (mg/dL)
231
226
222
Mean FPG (mg/dL)
-67.4
-80.0
-67.6
Mean starting dose (U)
12.1
15.2
14.6
Mean final dose (U)
17.7
17.7
24.6
Patients with hypoglycemia

(%)
11.4
13
1. American Diabetes Association 74th Scientific Sessions 2014; 2363-PO.

2. Diabetologia 2011 54 SUPPL. 1 (S408-S409)
3. CTDA Annual Meeting 2009; oral presentation.
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11.0
NA
Half of patients do not achieve HbA1C <7%

Proportion of patients at HbA1C <7%
75
Cross-sectional data from the

National Health and Nutrition
Examination Surveys (NHANES)
4,926 adults who self-reported a
previous diagnosis of diabetes
57.0
50
52.5
44.1
25
43.1
19881994
19992002
20032006
20072010
From 1988 to 2010, achievement of HbA1C <7% appeared to increase

over time but still remained low
In 20072010, only half of patients achieved HbA1C <7%
Only 78% of patients achieved HbA1C <8%
14
Casagrande S et al. Diabetes Care. 2013;36:2271-9

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Summary
Legacy Effect
(UKPDS)
Microvascular
Disease
(1997 2007)
Insulin Treatment
(ORIGIN)
Real World
Patients with A1C < 7%:
10.7%
What is the Barrier for HbA1c Achievement?

1.
2.
3.
15
Holman RR wt al., N Engl J Med 2008;359:1577-89.

American Diabetes Association 74th Scientific Sessions 2014; TW.TJO.16.04.03
2363-PO.
Potential causes of clinical inertia

Physicians and patients
Fear of hypoglycemia and weight gain
Physicians
Failure to appreciate the progressive nature of T2DM consequent to
-cell failure
Lack of understanding about the frequent failure of monotherapy
Lack of confidence
Poor recognition of the evidence that demonstrates the benefits of
early glycemic control
Reluctance to use combination therapy early after diagnosis
What is the Impact of Hypoglycemia?

Lovshin JA, Zinman B. Nat Rev Endocrinol. 2013;9:635-6
16
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(1) Reasons why health-care professionals and patients

might refrain from starting insulin treatment
90
80
Health care professional
70
Patients who are insulin nave
60
50
40
30
20
10
0
17
Avivit Cahn et al, Lancet Diabetes Endocrinol, 2015; 3: 63852

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(2) Fear of hypoglycemia is a major barrier

In clinical practice, fear of hypoglycemia is a common barrier to
optimal titration, adherence and achieving glycemic targets
with insulin
Fear
Fear of
of a
a new
new hypoglycemic
hypoglycemic episode
episode may
may lead
lead to
to
deterioration
deterioration of
of glycemic
glycemic control
control
Decreased
Decreased desire
desire
of
of tight
tight glycemic
glycemic
control
control
Reduced
Reduced
willingness
willingness to
to
intensify
therapy
intensify therapy
Poorer
Poorer
adherence
adherence to
to
diet
diet therapy
therapy
Compromised
Compromised
compliance
compliance for
for
taking
taking medication
medication
Patients
Patients who
who have
have had
had hypoglycemia
hypoglycemia tend
tend to
to target
target a
a higher
higher nightnighttime
time glucose
glucose level
level due
due to
to fear
fear of
of nocturnal
nocturnal hypoglycemia
hypoglycemia
Hypoglycemia
Hypoglycemia is
is a
a risk
risk factor
factor for
for later
later hyperglycemiahyperglycemiarelated
related complications
complications
Ahrn B. Vasc Health Risk Manag. 2013;9:155-163
18
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(3) Need for insulin regimens that are less restrictive

and burdensome with lower risk of hypoglycemia
Primary care physician
Specialist
A significant number of patients do not have

adequate blood glucose levels with insulin
treatment*
85%
I would treat my patients more aggressively

if there was no concern about
hypoglycemia*
72%
79%
International internet GAPP

survey
Involved 1,250 physicians who
treat patients with diabetes
P<0.05
90%
20
40
60
Percentage
80
P<0.05
100
*Strongly agree or somewhat agree (vs. strongly disagree, somewhat

disagree, neither, dont know)
GAPP, Global Attitudes of Patients and Physicians in Insulin Therapy ,Peyrot M et al. Diabet Med. 2012;29:682-689
19
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(4) For Patients:

Fear of hypoglycemia reduces patient adherence
Proportion of patients modifying insulin dose
to avoid future hypoglycemia
Leiter LA et al. Can J Diabetes 2005;29:186-192
20
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[SUMMARY] Sub-optimal insulin experiences steer

patients away from goal
85%
Primary care
physicians and
specialists
A significant number of
patients do not have
adequate blood glucose
levels with insulin treatment*
Peyrot M, et al. Diabetes Med 2012;29:682689.Brod M, et al. Curr Med Res Opin. 2012 Dec;28(12):1947
1958.Fidler C, et al. J Med Econ 2011;14:646655.Amiel SA, et al. Diabet Med 2008;25:245254.Leiter LA, et al.
Can J Diabetes
2005;29:186192.
GAPP,
Global Attitudes
of Patients and Physicians in Insulin Therapy ,Peyrot M et al. Diabet Med. 2012;29:682-689
21
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Unmet needs with basal insulin therapy

Clinical inertia cause a delay in insulin initiation and lack of
optimization in clinical practice15
Barriers that prevent insulin optimization including fear/risk of
hypoglycemia, lack of dose titration, poor adherence and persistence,
weight gain, lack of dosing flexibility, perceived lack of efficacy and
treatment satisfaction610
Hypoglycemia has a negative impact on patient care
Compromise glycemic control
Increase the risk of long-term complications8,1013
Negative consequences for adherence, persistence, well-being . 1417
1. Grunberger G. Diabetes Obes Metab. 2013;15 Suppl 1:1-5; 2. Owens DR. Diabetes Technol Ther. 2013;15:776-785; 3. Stone MA et al. Diabetes Care. 2013;36:262838;
22 Suppl
4. Khunti K et al. Diabetes Obes Metab. 2012;14:654-61; 5. Lovshin JA, Zinman B. Nat Rev Endocrinol. 2013;9:635-6; 6. Garber AJ. Diabetes Obes Metab. 2009;11
5:10-3;
7. Peyrot M et al. Diabetes Care. 2005;28:2673-9; 8. Ahrn B. Vasc Health Risk Man. 2013;9:155-163; 9. Peyrot M et al. Prim Care Diabetes. 2010;4 Suppl 1:S11-8;
10. Peyrot M et al. Diabet Med. 2012;29:682-689; 11. Seaquist ER et al. Diabetes Care. 2013;36:1384-95; 12. Zoungas S et al. N Engl J Med. 2010;363:1410-1418;
13. ORIGIN Investigators. Eur Heart J. 2013;34:3137-44; 14. Bron M et al. Postgrad Med. 2012;124:124-32; 15. Fidler C. J Med Econ. 2011;14:646-55; TW.TJO.16.04.03
Timeline for the development of basal insulins
1992
Glargine
1980
rDNA human
insulins
1922
First insulin
1920
1996
Detemir
2010
Degludec
2011
Glargine U300
1946
NPH
1930 1940 1950 1960 1970

1936
PZI
1950s
Lente family
1980
1990
2000
1988
NovoSol
Basal
2010
2010
LY2605541
Change in isoelectric point to wards neutral

pH
Acylation of insulin which fatty acids C14-C16
PEGlated insulin
David R. Owens et al. Diabetes Metab Res Rev 2014; 30: 104119.
23
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Clinical Pharmacology of
Insulin Glargine U300
24
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Gla-U300 is a new long-acting basal insulin with a more

even and prolonged PK/PD profile vs Gla-U100
More even and prolonged
PK/PD profile
Insulin concentration, U/mL
25
20
15
10
5
0
Gla-U300
Gla-U100
0
12
18
24
30
36
Glucose infusion rate (GIR), mg/kg/min

3
Gla-U100
Insulin
Glargine
-U100
Insulin
Glargine
-U300
Gla-U300
1
0
0
12
18
24
30
36
Blood glucose, mg/dL

160
Gla-U100
140
120
Gla-U300
100
0
12
18
24
30
36
Time, h
25
Steinstraesser A et al. Diabetes Obes Metab. 2014;16:873-6; Becker RHA et al. Diabetes Care. 2014 Aug 22. pii: DC_140006. [Epub ahead of print]
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Even distribution of glucose-lowering effect

with Gla-U300
Even distribution of exposure and glucodynamics within-day
fluctuation
53%
GIR, mg/kg/min
47%
0-12 hours
12-24 hours
2
Average GIR
1
0
29%
24%
0-6 hours
6-12 hours
23%
12-18 hours
23%
18-24 hours
Crossover euglycemic clamp study of Gla-U300 0.4 U/kg in 50 patients

with T1DM
AUC, area under the curve; GIR, body weight standardized glucose infusion rate; INS, serum insulin concentration; T1DM, type 1
diabetes mellitus
Adapted from Becker RH et al. Diabetes Obes Metab. 2015;17:261-7 (main article and Supplementary Table 1)
26
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T1DM
Average plasma glucose during the last 2 weeks of

treatment by time of day: CGM study in patients with T1DM
Gla-U300
Average 24-hour glucose

profiles showed a more
constant glucose level
with Gla-U300 vs GlaU100
Mean glucose profiles appeared more
constant with Gla-U300 compared with
Gla-U100, independent from the time of
injection (morning or evening)
Gla-U100
Gla-U300
11
10
9
8
Morning
7
0
10
Evening
12
14
16
18
20
22
24
20
22
24
Gla-U100
11
10
9
8
Morning
7
0
10
Evening
12
14
16
18
Time, h
27
Bergenstal RM, et al. EASD, Vienna

2014
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EDITION Program
28
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EDITION program
Testing Gla-U300 vs Gla-U100 in several populations

T2DM
T1DM
EDITION 2
EDITION 1
BB
N=807
BOT
Basal insulin plus mealtime

bolus insulin (fast-acting
analogue)
EDITION 3
BOT
N=878
Basal insulin plus OAD (excl.

SU)
BB
N=241
Basal insulin plus OAD
N=549

analogue)
EDITION JP 2
BOT
Basal insulin plus OAD (excl.

SU) and/or GLP-1 receptor
agonists
EDITION 4
N=811
EDITION JP 1
BB
N=243

analogue)
All Phase 3, 18 years

BB, basal-bolus therapy; BOT, basal only therapy
Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Jrvinen H et al. Diabetes Care. 2014 Sep 5. pii: DC_140990 [Epub ahead of print];
29
Bolli GB et al. Poster presentation at
EASD 2014; Abstract 947; Terauchi Y et al. Poster presentation at EASD 2014; Abstract 976; Home PD et al. Oral presentation at EASD 2014;
Abstract 148; Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975
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EDITION study design is consistent across the program

Randomized 1:1, open-label, parallel-group, multinational
studies
EDITION program built with similar study design across trials
to
U300
U300 OADs
OADs
confirm results
Mealtime
Mealtime insulin
insulin
Participants
Participants
Randomized
Randomized
(1:1)
(1:1)
U100
U100 OADs
OADs
Mealtime
Mealtime insulin
insulin
6
months
6-month
Extension period
Non-inferiority
Non-inferiority to
to Gla-U100
Gla-U100 in
in HbA
HbA1C
1C
reduction
reduction was
was the
the primary
primary endpoint
endpoint in
in all
all
trials
trials
Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Jrvinen H et al. Diabetes Care. 2014 Sep 5. pii: DC_140990 [Epub ahead of print]; Bolli GB et al.
Poster presentation at
30
EASD 2014; Abstract 947; Terauchi Y et al. Poster presentation at EASD 2014; Abstract 976; Home PD et al. Oral presentation at EASD 2014; Abstract
148;
Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975; Riddle MC et al. Poster presentation at EASD 2014; Abstract 980; Yki-Jrvinen H et al.
Poster presentation at
TW.TJO.16.04.03
EASD 2014; Abstract 946
EDITION: T2DM studies
31
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EDITION program

T2DM
T1DM
EDITION 2
EDITION 1
N=807
BB
Basal insulin plus

mealtime bolus insulin
(fast-acting analogue)
EDITION 3
BOT
N=878

(excl. SU) and/or GLP-1
receptor agonists
BOT
N=811

(excl. SU)
EDITION JP 2
BOT
EDITION 4
N=241
BB
N=549
Basal insulin plus

EDITION JP 1
BB
N=243
Basal insulin plus


32
Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Jrvinen H et al. Diabetes Care. 2014 Sep 5. pii: DC_140990 [Epub ahead of print]; Bolli GB et al. Poster presentation at
EASD 2014; Abstract 947; Terauchi Y et al. Poster presentation at EASD 2014; Abstract 976; Home PD et al. Oral presentation at EASD 2014; Abstract 148; Matsuhisa M et al.
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Poster presentation at EASD 2014; Abstract 975
Baseline characteristics of T2DM studies

Mean (SD) unless otherwise stated
EDITION 1
EDITION 2
EDITION 3
EDITION JP 2
N=807
N=811
N=878
N=241
60.0 (8.6)
58.2 (9.2)
57.7 (10.1)
60.8 (11.4)
52.9
45.9
57.7
61.0
36.6 (6.4)
34.8 (6.4)
33.0 (6.7)
25.3 (3.8)
106.3 (20.8)
98.3 (21.6)
95.3 (22.9)
66.7 (13.2)
Duration of diabetes, years
15.8 (7.5)
12.6 (7.0)
9.84 (6.4)
14.0 (8.3)
Duration of basal insulin treatment,

years
6.6 (4.8)
3.8 (3.5)
2.45 (2.4)
Basal / total insulin dose before the

study, U/kg
0.67 / 1.2
0.67 / -
0.24 / -
Prior use of metformin, %
57.4
95.1
91.3
58.1
HbA1C, %
8.15
8.24
8.54
8.0
Age, years
Male, %
BMI, kg/m
Mean weight, kg
SUs were not permitted post-randomization in EDITION 1, EDITION 2, EDITION 3 but were allowed in EDITION JP 2
Data on file, EDITION 1 CSR pg 62-68; EDITION 2 CSR pg 62-68; EDITION 3 CSR pg 73-78; EDITION 4 CSR pg 75-82
EDITION JP 2 CSR, pg 28, 75-82
33
Primary endpoint of HbA1C non-inferiority to Gla-U00

at Month 6 across all T2DM studies
EDITION
1
EDITION
2
Mean (SE) HbA1c, %

9.0
8.5
Difference: -0.00%
95% CI -0.11 to
0.11
8.0
9.0
8.5
8.0
Difference: -0.01%
95% CI -0.14 to 0.12
Gla-U100
7.5
7.0
Baseline
EDITION
3
7.5
Gla-U100
Gla-U300
W12
LOCF
M6
7.0
Baseline
Gla-U300
LOCF
W12
M6
EDITION JP
2
9.0
9.0
Difference: 0.04%
95% CI -0.09 to
0.17
8.5
8.0
8.5
Difference: 0.10%
95% CI -0.08 to 0.27
8.0
Gla-U100
7.5
7.0
Baseline
Gla-U100
Gla-U300
W12
M6
7.5
7.0
Baseline
Gla-U300
LOCF
W12
Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Jrvinen H et al. Diabetes Care. 2014 Sep 5. pii: DC_140990
[Epub ahead of print]; Bolli GB et al. Poster presentation at EASD 2014; Abstract 947 Available at:
http://www.easdvirtualmeeting.org/resources/19556 Accessed September 2014; Terauchi Y et al. Poster
presentation at EASD 2014; Abstract 976 Available at: http://www.easdvirtualmeeting.org/resources/19078
M6
3
4
Incidence of confirmed (70 mg/dL [3.9 mmol/L]) or severe

hypoglycemia in T2DM studies at Month 6
Nocturnal (00:0005:59 h)
Baseline to Month 6
Favors Favors
Gla-U300 Gla-U100
Favors
Gla-U300
Favors Favors
Gla-U300 Gla-U100
EDITION 1
BB
Week 9 to Month 6*
Baseline to Week 8
Favors
Gla-U100
0.79 (0.64 to 0.98)
0.78 (0.68 to 0.89)
0.79 (0.67 to 0.93)
EDITION 2
BOT switch
0.71 (0.58 to 0.86)
0.53 (0.39 to 0.72)
0.77 (0.61 to 0.99)
EDITION 3
BOT start
0.76 (0.59 to 0.99)
0.74 (0.48 to 1.13)
0.89 (0.66 to 1.20)
0.62 (0.44 to 0.88)
0.83 (0.45 to 1.52)
0.58 (0.40 to 0.85)
EDITION JP 2
BOT switch
0.1
1
Relative risk (95% CI)
10
0.1
1
10
0.1
1
10
*mITT population for main secondary endpoint for EDITION 1, 2 and 3; safety population for the other timepoints
Relative risk and 95% CI based on % of participants with 1 event of one confirmed (70 mg/dL [3.9 mmol/L]) or severe hypoglycemia
BB, basal-bolus therapy; BOT, basal only therapy; mITT, modified intention-to-treat; T2DM, type 2 diabetes mellitus
Adapted from Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Jrvinen H et al. Diabetes Care. 2014;37:3235-43; Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94;
Data on file, EDITION JP 2 CSR (6 months) Appendix 15-3-1-ae-6-month.pdf pg 16
NOT FOR PROMOTIONAL USE DO NOT DISTRIBUTE

SAGLB.TJO.15.12.0922
Main
secondary
endpoint*
35

Any time of day (24 h)
Baseline to Month 6
Favors Favors
Gla-U300 Gla-U100
Favors Favors
Gla-U300 Gla-U100
Week 9 to Month 6
Baseline to Week 8
Favors Favors
Gla-U300 Gla-U100
EDITION 1
BB
0.93 (0.88 to 0.99)
0.86 (0.78 to 0.94)
0.96 (0.89 to 1.04)
EDITION 2
BOT switch
0.90 (0.83 to 0.98)
0.78 (0.69 to 0.89)
0.91 (0.82 to 1.02)
EDITION 3
BOT start
0.88 (0.77 to 1.01)
0.83 (0.67 to 1.03)
0.86 (0.74 to 1.00)
EDITION JP 2
BOT switch
0.86 (0.73 to 1.01)
0.69 (0.52 to 0.91)
0.84 (0.70 to 1.01)
0.1
1
10
0.1
1
10
0.1
1
Safety population
Relative risk and 95% CI based on % of participants with 1 event of one confirmed (70 mg/dL [3.9 mmol/L]) or severe hypoglycemia
BB, basal-bolus therapy; BOT, basal only therapy; T2DM, type 2 diabetes mellitus
Data on file, EDITION JP 2 CSR (6 months) Appendix 15-3-1-ae-6-month.pdfNOT
pg 14 FOR PROMOTIONAL USE DO NOT DISTRIBUTE
10
36
Rate of nocturnal (00:0005:59 h) confirmed (70 mg/dL [3.9

mmol/L]) or severe hypoglycemia in T2DM studies at Month 6
2.5
EDITION 1
BB
Cumulative mean numbers of confirmed

(70 mg/dL [3.9 mmol/L]) or severe events
2.0
Gla-U100
Gla-U300
2.5
2.0
1.5
1.5
1.0
1.0
Rate ratio 0.75 (0.58 to

0.95)
0.5
0.0
EDITION 2
BOT switch

0.77)
0.5
0.0
12
16
20
24

1.48)
12
16
20
24
28
EDITION JP
2
BOT switch
EDITION 3
BOT start

0.96)
2
2
1
0
0
12
16
20
Time, weeks
24
28
12
16
20
24
28
Time, weeks
37
37
Safety population; rate ratio and 95% CI are based on annualized rates per patient-year for confirmed (70 mg/dL [3.9 mmol/L]) or severe hypoglycemia
Adapted from Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Jrvinen H et al. Diabetes Care. 2014;37:3235-43; Bolli GB et al. Diabetes Obes Metab 2015;17:386-394 (main article and Supplementary Figure 3);
Data on file, EDITION JP 2 CSR (6 months) pg 147; EDITION JP 2 Ad-hoc analyses (6 months) efc12512-hypo-adhoc-jp pg 8
TW.TJO.16.04.03
Rate of confirmed (70 mg/dL [3.9 mmol/L]) or severe

hypoglycemia at any time of day (24 h) in T2DM studies at Month 6
14
EDITION 1
BB
12
Gla-U100
Gla-U300

10
12
EDITION 2
BOT switch
10
8
8
6
6
4

1.13)
Rate ratio 0.77 (0.63

to 0.96)
2
0
0
0
16
12
16
20
14
12

0.99)
10
12
16
12
24
28
Rate ratio 0.64 (0.43

to 0.96)
10
20
EDITION JP
2
BOT switch
16
EDITION 3
BOT start
14
24
0
0
12
16
20
Time, weeks
24
28
12
16
20
24
28
Time, weeks
Data on file, EDITION JP 2 CSR (6 months) pg 145; EDITION JP 2 Ad-hoc analyses (6 months) efc12512-hypo-adhoc-jp pg 5
38
38
TW.TJO.16.04.03
EDITION 1 & 2 sub-studies: Flexible vs fixed

dosing
3-month flexibility sub-studies embedded at 6 to 9 months into
EDITION 1 and EDITION 2
In the sub-studies, participants using Gla-U300 were randomized
(1:1) at Month 6 to continue the fixed-dosing regimen or to use
flexible-dosing intervals
Fixed-dosing regimen: each basal insulin dose injected at the same time each
evening
Flexible-dosing arm: each insulin dose injected within 3 h of preferred evening
injection time (24 3 h) and at the maximum interval (exactly 3 h earlier or
later than the injection reference time) on at least 2 days each week
Gla-U300 once
daily every
24 h
Randomize
d
1:1
Month 6
Sub-study randomization
Gla-U300 once
daily every
24 h
Gla-U300 once
daily every
24 3 h
Month 9
End of sub-study
39
Jeandidier N et al. Poster presentation at EASD 2014; Abstract 961 Available at:
http://www.easdvirtualmeeting.org/resources/18792 Accessed September 2014
TW.TJO.16.04.03
Similar baseline characteristics

EDITION 1
Characteristics
EDITION 2
Flexible dosing
Fixed dosing
Flexible dosing
Fixed dosing
56
53
45
44
Mean (SD) age, years
61.0 (7.4)
59.1 (9.6)
58.4 (8.2)
57.2 (10.0)
Male, n (%)
24 (42.9)
25 (47.2)
22 (48.9)
22 (50.0)
7.21 (0.91)
7.17 (0.89)
7.41 (0.96)
7.47 (1.05)
Mean (SD) HbA1C, %
40
TW.TJO.16.04.03
Similar glycemic control with different dosing

regimens
EDITION 1
EDITION 2
LS mean change (SE) in HbA1C from Month 69, %
0.4
Flexible
Fixed
0.2
LS mean change (SE) in clinical FPG from Month 69,

mmol/L
Flexible
Fixed
-0.2 2
1.5
1
-0.4
0.5
0
-0.5
-1
-1.5
41
TW.TJO.16.04.03
Similar hypoglycemia with different dosing

regimens
EDITION 1
EDITION 2
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
Confirmed or severe at any time (70 mg/dL [3.9 mmol/L])
Flexible dosing
Fixed dosing
Confirmed or severe at any time (70 mg/dL [3.9 mmol/L])
42
TW.TJO.16.04.03
EDITION program

T2DM
EDITION 2
EDITION 1
N=807
BB
Basal insulin plus

BOT
BOT
EDITION JP 2

(excl. SU) and/or GLP-1
receptor agonists
BOT
EDITION 4
N=811

(excl. SU)
EDITION 3
N=878
T1DM
N=241
BB
N=549
Basal insulin plus

EDITION JP 1
BB
N=243
Basal insulin plus


43
Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Jrvinen H et al. Diabetes Care. 2014 Sep 5. pii: DC_140990 [Epub ahead of print]; Bolli GB et al. Poster presentation at
EASD 2014; Abstract 947; Terauchi Y et al. Poster presentation at EASD 2014; Abstract 976; Home PD et al. Oral presentation at EASD 2014; Abstract 148; Matsuhisa M et al.
TW.TJO.16.04.03
Poster presentation at EASD 2014; Abstract 975
EDITION: T1DM studies
44
TW.TJO.16.04.03
Baseline characteristics of T1DM studies

Mean (SD) unless otherwise stated
EDITION 4
EDITION JP 1
N=549
N=243
47.3 (13.7)
45.2 (14.6)
57.0
46.1
BMI, kg/m
27.6 (5.1)
23.5 (3.6)
Mean weight, kg
81.8 (18.7)
62.5 (11.7)
Duration of diabetes, years
21.0 (12.9)
13.0 (8.8)
0.38 / 0.33 / 0.72
0.29 / 0.45 / 0.74
8.1
8.1
Age, years
Male, %
Basal / mealtime / total insulin dose, U/kg

HbA1C, %
Data on file, EDITION 4 CSR, pg 78, 80-83, 85

Data on file, EDITION JP 1 CSR, pg 70, 73-75
45
TW.TJO.16.04.03
Primary endpoint of HbA1C non-inferiority to Gla-U100

at Month 6 in both T1DM studies
EDITION
4
EDITION JP
1
Mean (SE) HbA1c, %

9.0
8.5
Difference: 0.04%
95% CI -0.10 to 0.19
8.0
7.5
7.0
Baseline
9.0
Gla-U300
Week 12
8.5
8.0
7.5
Gla-U100
Month 6
Difference: 0.13%
95% CI -0.03 to 0.29
7.0
Baseline
Gla-U300
Gla-U100
LOCF
Week 12
Month 6
Home PD et al. Oral presentation at EASD 2014; Abstract 148 Available at: http://www.easdvirtualmeeting.org/resources/16864 Accessed September
2014
Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975 Available at: http://www.easdvirtualmeeting.org/resources/18532 Accessed
September 2014
46
TW.TJO.16.04.03
Confirmed (70 mg/dL [3.9 mmol/L]) and/or severe nocturnal hypoglycemia in T1DM studies
Gla-U300
Gla-U100
EDITION
4
EDITION JP
1
Participants with 1 confirmed (70 mg/dL [3.9 mmol/L])

and/or severe hypoglycemia (%)
100
80
60
Participants with 1 confirmed (70 mg/dL [3.9

mmol/L]) and/or severe hypoglycemia (%)
100
RR 0.98
(0.88-1.09)
RR 0.82
(0.70-0.96)
RR 1.06
(0.92-1.23)
80
RR 0.84
(0.70-1.00)
RR 0.71
(0.56-0.91)
60
40
40
20
20
RR 0.85
(0.73-0.99)
0
Baseline to month 6 Baseline to week 8 Week 9 to month 6
Baseline to month 6 Baseline to week 8 Week 9 to month 6
Home PD et al. Poster presentation at ADA 2014; Abstract 80-LB Available at: http://ada.apprisor.org/epsAbstractADA.cfm?id=1 Accessed June 2014
Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975 Available at: http://www.easdvirtualmeeting.org/resources/18532 Accessed September 2014
47
TW.TJO.16.04.03

Favors Favors
Gla-U300 Gla-U100
EDITION 4
EDITION JP 1
Favors Favors
Gla-U300 Gla-U100
Baseline to Month 6
0.98 (0.88 to 1.09)
1.00 (0.95 to 1.04)
Baseline to Week 8
0.82 (0.70 to 0.96)
0.98 (0.92 to 1.04)
Week 9 to Month 6
1.06 (0.92 to 1.23)
0.98 (0.91 to 1.06)
Baseline to Month 6
0.85 (0.73 to 0.99)
0.99 (0.95 to 1.04)
Baseline to Week 8
0.71 (0.56 to 0.91)
0.91 (0.84 to 0.99)
Week 9 to Month 6
0.84 (0.70 to 1.00)
1.01 (0.95 to 1.08)
0.1
10
0.1
Safety population; relative risk and 95% CI based on % of participants with 1 event of one confirmed (70 mg/dL [3.9 mmol/L]) or severe hypoglycemia
T1DM, type 1 diabetes mellitus
Home PD et al. Diabetes Care. 2015 Jun 17. pii: dc150249. [Epub ahead of print] (Supplementary Table 2); Data on file, EDITION JP 1 CSR (6 months) Appendix 15-3-1-ae-6-month.pdf pg 7, 9

10
48
Rate of confirmed (70 mg/dL [3.9 mmol/L]) or severe

45
EDITION 4
Gla-U100
Gla-U300
EDITION 4
40
35
30

25
20
15
10
Rate ratio 0.90 (0.71 to 1.14)
0
4
0
10
12
16
20
24
0
28
0
60
EDITION JP 1
Rate ratio 1.09 (0.94 to 1.25)
48
42
36
30
24
18
12
Rate ratio 0.66 (0.48 to 0.92)
1
0
12
16
20
24
28
EDITION JP 1
54
Rate ratio 0.80 (0.65 to 0.98)
6
0
12
16
Time, weeks
20
24
28
12
16
T1DM, type 1 diabetes mellitus
The steep increase in the Toujeo group during the last 8 days of the main 6-month treatment period in EDITION JP 1 is explained by the very low number of patients exposed to
treatment during this time who experienced only 1 event on each of Day 187, Day 189 and Day 190
Adapted from Home PD et al. Diabetes Care. 2015 Jun 17. pii: dc150249. [Epub ahead of print] (main article and Supplementary Figure 3);
Data on file, EDITION JP 1 CSR (6 months) pg 128, 130; EDITION JP 1 JCTD-Module 2.7.4-2.7.4.8.2-EN (6 months) pg 109, 123

20
24
28
Time, weeks
49
Overview of hypoglycemia: Gla-U300 vs Gla-U100

EDITION 4
EDITION JP 1
Start to Week 8
0.65 (0.29 to 1.45)
0.50 (0.13 to 1.94)
Week 9 to Month 6
0.79 (0.36 to 1.71)
0.99 (0.29 to 3.31)
Severe hypoglycemia
Severe and/or confirmed hypoglycemia 70 mg/dL (3.9 mmol/L) at any time (24 h)
Start to Week 8
0.98 (0.92 to 1.04)
0.91 (0.84 to 0.99)
Week 9 to Month 6
0.98 (0.91 to 1.06)
1.01 (0.95 to 1.08)
Severe and/or confirmed nocturnal hypoglycemia 70 mg/dL (3.9 mmol/L)

Start to Week 8
0.82 (0.70 to 0.96)
0.71 (0.56 to 0.91)
Week 9 to Month 6
1.06 (0.92 to 1.23)
0.84 (0.70 to 1.00)
% of patients with at least one hypoglycemia event of the specified category

Data on file, saf_hypo_ph2_3, pg 185, 219, 273
Home PD et al. Poster presentation at ADA 2014; Abstract 80-LB Available at: http://ada.apprisor.org/epsAbstractADA.cfm?id=1 Accessed June 2014
Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975 Available at: http://www.easdvirtualmeeting.org/resources/18532 Accessed September 2014
Data on file, JP-1efc12449_15_3_1_ae_data pg 6,7
50
TW.TJO.16.04.03
Similar AE profile of Gla-U300 and Gla-U100 at Month 6

T2DM studies
T1DM studies
AE, adverse event; BB, basal-bolus therapy; BOT, basal only therapy; T1DM,
EDITION TEAEs, treatmenttype 1 diabetes mellitus;
T2DM,2type 2 diabetes mellitus;
EDITION
EDITION
EDITION 3
JP 2
EDITION
emergent
adverse 1
events BOT
EDITION 4
Proportion
of
BB
BOT start
BOT
JP 1
Similar1 safety
profiel
switch
Data on file, EDITION
CSR
(6 months)
pg 125; EDITION
2
CSR
(6
months)
pg
switch
patients,
metabolite
124; %
EDITION 3M1
CSR
(6 months) pg 139; EDITION JP 2 CSR (6 months) pg 152;
EDITION 4 CSR (6 months) pg 158; EDITION JP 1 CSR (6 months) pg 136
Gla300
Gla100
Gla300
Gla100
Gla300
Gla100
Gla300
Gla100
Gla300
Gla100
Gla300
Gla100
56.4
54.2
58.8
50.7
56.8
55.9
58.3
56.7
60.9
58.2
62.3
64.5
Serious
TEAEs
6.4
5.2
3.7
3.7
5.5
5.9
4.2
3.3
6.2
8.0
2.5
2.5
TEAEs
leading to
discontinuati
on
1.5
1.7
1.5
1.0
1.1
1.1
2.5
0.8
1.1
1.1
0.8
TEAEs
leading to
death
0.2
0.5
0.5
0.2
0.2
0.4
TEAEs
mITT population
BB, basal-bolus therapy; BOT, basal only therapy; mITT, modified intention-to-treat; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Jrvinen H et al. Diabetes Care. 2014;37:3235-43; Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94;
Data on file, EDITION JP 2 CSR (6 months) pg 104; Home PD et al. Diabetes Care. 2015 Jun 17. pii: dc150249. [Epub ahead of print];
Data on file, EDITION JP 1 CSR (6 months) pg 93
51
51
TW.TJO.16.04.03
Basal insulin doses at Month 6

EDITION 1
BB
Basal insulin dose, U/kg/day
1.00
EDITION 2
BOT switch
EDITION 3
BOT start
EDITION JP 2
BOT switch
EDITION 4
EDITION JP 1
0.98
Gla-U300
0.93
0.88
0.85
Gla-U100
0.75
T2DM
0.62
T1DM
0.53
0.47
0.50
0.40
0.35
0.35
0.30
0.29
0.25
0.00
mITT population
BB, basal-bolus therapy; BOT, basal only therapy; mITT, modified intention-to-treat; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Jrvinen H et al. Diabetes Care. 2014;37:3235-43; Bolli GB et al. Diabetes Obes Metab. 2015;17:386-94;
Data on file, EDITION JP 2 CSR (6 months) pg 104; Home PD et al. Diabetes Care. 2015 Jun 17. pii: dc150249. [Epub ahead of print];
Data on file, EDITION JP 1 CSR (6 months) pg 93

52
Weight changes at Month 6
Change from baseline to Month 6 (LOCF)

EDITION 1
BB
EDITION 2
BOT switch
EDITION 3
BOT start
EDITION JP 2
BOT switch
EDITION 4
EDITION JP 1
Gla-U300
Mean (SD) weight change from

baseline, kg
1.5
1.0
Gla-U100
0.9 0.9
(3.2) (3.1)
0.9
1.0
0.7
T1DM
0.5
0.4
0.5
T2DM
0.7
0.4
0.3
0.1
0.0
-0.1
-0.5
-0.6
-1.0
-1.5
Safety population
BB, basal-bolus therapy; BOT, basal only therapy; LOCF, last observation carried forward; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
Data on file, EDITION 1 CSR (6 months) pg 153; Yki-Jrvinen H et al. Diabetes Care. 2014;37:3235-43; Data on file, EDITION 3 CSR (6 months) pg 170;
EDITION JP 2 CSR (6 months) pg 167; EDITION 4 CSR (6 months) pg 188; EDITION JP 1 CSR (6 months) pg 149

53
Summary
Gla-U300 has insulin glargine at its core
Gla-U300 has a more even and prolonged PK/PD profile vs
Gla-U100 with effects lasting beyond 24 hours and with low
within-day fluctuation
Using CGM, Gla-U300 provided similar glucose control to GlaU100 with more constant glucose profiles and lower glucose
variability
54
TW.TJO.16.04.03
Summary
In the EDITION program, Gla-U300 vs Gla-U100 exhibited:
Similar HbA1C reductions in T2DM and T1DM
Significantly lower rates of confirmed or severe hypoglycemia at
any time of day in EDITION 2, 3 and JP 2 but not in EDITION 1 and
significantly lower rates at night in EDITION 1, 2 and JP 2 but not
in EDITION 3 (T2DM studies)
Significantly lower rate of confirmed hypoglycemia at any time of
day or at night in EDITION JP 1 and similar in EDITION 4 (T1DM
studies)
Provides flexibility of insulin injections to an individuals changing
daily lifestyle patterns in sub-studies of EDITION 1 and 2
Slight increase in basal insulin dose
55
TW.TJO.16.04.03

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Advances in Diabetes Care:

Next Generation Basal insulin

PLEASE TAKE NOTE

Current Unmet Needs With Insulin

What is the importance of insulin therapy?

UKPDS: Decrease in HbA1c results in a reduction in the

*p < 0.0001 vs. baseline; #p = 0.035.

Lower extremity amputation or fatal peripheral vascular disease.

Stratton I, et al. BMJ 2000;321:405-12.

UKPDS: Legacy effect of earlier intensive glucose control

Any diabetes-related endpoint

RRR = relative risk reduction, p = log rank

Holman RR wt al., N Engl J Med 2008;359:1577-89.

Efficacy of basal insulin in T2D patients uncontrolled

RCTs insulin glargine group:

ADA-EASD position statement update:

Inzucchi SE, et al. Diabetes Care 2015;38:140-9.

2015 ADA EASD position statement: Management of

Inzucchi SE, et al. Diabetes Care 2015;38:140-9.

ORIGIN: Insulin provides long-term near-normal

Gla-U100 had a neutral effect on the primary CV endpoints vs standard care

ORIGIN trial invest. New Engl J Med 2012;367:319-328.

Insulin provides sustained HbA1C reduction

Insulin Treatment has the long-term benefits

ORIGIN trial invest. New Engl J Med 2012;367:319-328.

Real World Study

Poland Germany China Spain Canada Portugal Italy

SOLVE, Study of Once Daily Levemir

Survey of Basal Insulin Use for T2D in Taiwan

Mean age (year)

Mean diabetes duration

Mean body weight (kg)

Mean baseline A1C (%)

Mean A1C (%)

Patients with A1C < 7% (%)

Mean baseline FPG (mg/dL)

Mean FPG (mg/dL)

Mean starting dose (U)

Mean final dose (U)

Patients with hypoglycemia

1. American Diabetes Association 74th Scientific Sessions 2014; 2363-PO.

Half of patients do not achieve HbA1C <7%

Cross-sectional data from the

From 1988 to 2010, achievement of HbA1C <7% appeared to increase

Casagrande S et al. Diabetes Care. 2013;36:2271-9

Patients with A1C < 7%:

What is the Barrier for HbA1c Achievement?

Holman RR wt al., N Engl J Med 2008;359:1577-89.

Potential causes of clinical inertia

What is the Impact of Hypoglycemia?

(1) Reasons why health-care professionals and patients

Health care professional

Patients who are insulin nave

Avivit Cahn et al, Lancet Diabetes Endocrinol, 2015; 3: 63852

(2) Fear of hypoglycemia is a major barrier

(3) Need for insulin regimens that are less restrictive

A significant number of patients do not have

I would treat my patients more aggressively

International internet GAPP

*Strongly agree or somewhat agree (vs. strongly disagree, somewhat

(4) For Patients:

Leiter LA et al. Can J Diabetes 2005;29:186-192

[SUMMARY] Sub-optimal insulin experiences steer