Bydureon

1. Exenatide Once Weekly (QW)
Overview of Clinical Profile and Long-term Data
Bydureon
Alex Aizikovich MD

2. • Diabetes* worldwide prevalence 2013: ~382 million people1
• Prevalence (%) estimates of diabetes * (20-79 years, 2013) ¹a
Diabetes—a growing global epidemic
Of all cases of
diabetes, >90%
of cases are
type 2 diabetes2
EU: 6.8%
North
America
& Canada
9.6%
* All cases of diabetes, including type 1 and type 2 diabetes, and impaired glucose tolerance (IGF), in patients aged 20-79 years.
1. International Diabetes Federation. IDF Diabetes Atlas, 6th ed. Brussels, Belgium: International Diabetes Federation, 2013. 2. Pi-Sunyer FX. Postgrad Med. 2009;121(5):94-107.
Israel:
6.6%

3. Association between Decrease in HbA1C and
Reduction of Complications
Deaths related
to diabetes*
21%
Stratton IM et al. BMJ 2000; 321: 405–412.
Microvascular
complications e.g.
kidney disease and
blindness*
37%
12%
Amputation or fatal
peripheral blood vessel
disease*
43%
Stroke**
Heart attack*
14%
* p<0.0001
** p=0.035
1%
HbA1c

4. The History of Treatment for Type 2 Diabetes
Adapted from: Kahn et al. lancet, 2014

5. Management of Hyperglycemia in Type 2 Diabetes, 2015:
Inzucchi et al Diabetes care 2015

7. Diabetes Treatment Algorithm – The National
Council of Diabetes
BMI<30 35>BMI>30 BMI>35
DPP-4 inhibitor/ SGLT2
Inh /Acarbose
(Consider GLP-1 RA)
GLP-1 RA
SGLT2 Inh
(DPP-4 inhibitors)
GLP-1 RA
Bariatric surgery
High post prandial High fasting glucose
Su/Glinids – Rapid/mix insulin
(consider pioglitazon)
Basal insulin
(consider pioglitazon)
Life style intervention +/-metformin
A1c >8.5: Consider
combination
therapy
A1c>9:
consider insulin
HbA1c not at target (3-6 months):
Intensification of insulin regimen (if BMI>30 consider Metabolic Surgery)
HbA1c not at target (3-6 months) Add:
Stage
3
The national council of diabetes 2015
Stage
1
Stage
2
Stage
4

8. Type 2 diabetes—visceral adipose tissue (VAT)
is a major cardiovascular risk factor
1. Carr DB, et al. Diabetes. 2004;53(8):2087-2094. 2. Eeg-Olofsson K, et al. Diabetologia. 2009;52(1):65-73. 3. De Koning L, et al. Eur
Heart J. 2007;28(7):850-856.

9. Met DPP4i SGLT2i GLP1RA TZD AGI SU/ GLN Insulin
Hypo Neutral Neutral Neutral Neutral Neutral Neutral Moderate-
severe/
mild
Moderate-
severe
Weight Slight loss Neutral Loss Loss Gain Neutral Gain Gain
Renal/
GU
Contraindicate
d stage 3B, 4,5
Dose
adjustm
ent
maybe
required
Infections Exenatide
BID
contraindicat
ed CrCl<30
May
worsen
fluid
retentio
n
Neutral More
hypo risk
More hypo
risk & fluid
retention
GI AE Moderate Neutral Neutral Moderate Neutral Moderate Neutral Neutral
CHF Neutral Neutral Neutral Neutral Moderat
e
Neutral Neutral Neutral
CVD Benefit Neutral Increased
LDL
Neutral Neutral Neutral ? Neutral
Bone Neutral Neutral Neutral Neutral Moderat
e bone
mass
loss
Neutral Neutral Neutral
Profiles of antidiabetic agents
Few AE or possible benefits Use with precaution Likelihood of adverse events
Adapted from Garber et al. AACe comprehensive diabetes management algorithm 2013.

10. GLP1 has multiple direct effects on human physiology
Insulin secretion2,3
(glucose-
dependent) and
beta-cell sensitivity
Insulin synthesis4
Glucagon secretion3
(glucose-
dependent)
Pancreas
Cardiovascular system
Systolic blood pressure8
1. Holst JJ et al. Trends Mol Med 2008;14:161–168; 2. Flint A et al. Adv Ther 2011;28:213–226; 3. Degn K et al. Diabetes
2004;53:1187–1194; 4. Baggio LL & Drucker DJ. Gastroenterology 2007;132:2131‒2157; 5. Horowitz M et al. Diabetes Res
Clin Pract 2012;97:258‒266; 6. Vilsbøll T et al. BMJ 2012;344:d7771; 7. Niswender K et al. Diabetes Obes Metab
2013;15:42‒54; 8. Fonseca V et al. Diabetes 2010;59(suppl 1):A79 (296-OR).
Liver
Hepatic glucose
output4
Brain
Body weight:5‒7
Satiety
Energy intake

11. Pharmacokinetic profiles: short- vs. long-acting GLP1
Category Agent Half-life Cmax
Short-
acting
<24 hours
Exenatide
BID1 2.4 hours 2 hours
Lixisenatide2 2.7–4.3 hours
1.25–2.25
hours
Long-
acting
≥24 hours
Liraglutide3 13 hours 8–12 hours
Dulaglutide4 90 hours 24–48 hours
Albiglutide5,6 6–7 days 3–5 days
Exenatide
OW7 7–14 days 6–7 weeks
1. Byetta® Summary of Product Characteristics, July 2012
2. Christensen et al. IDrugs 2009;12:503–13
3. Victoza® Summary of Product Characteristics, November 2012
4. Barrington et al. Diabetes Obes Metab 2011;13:434–8
5. Bush et al. Diabetes Obes Metab 2009;11:498–505
6. Matthews et al. J Clin Endo Metab 2008;93:4810–17
7. Fineman et al. Clin Pharmacokinet 2011;50:65–74
Increasingprotraction
BID, twice daily; OW, once weekly

12. Physiologic profiles: short- vs. long-acting GLP-1

13. Exenatide Improves Type 2 Diabetes Defects
Across the Fasting and Prandial States
1. Aronoff et al. Diabetes Spectrum. 2004;17(3):183-190. 2. Fehse et al. J Clin Endocrinol Metab. 2005;90(11):5991-5997.
3. Drucker et al. Lancet. 2006;368(9548):1696-1705.
Incretin actions
Incretin
defect in
T2DM1 Exenatide1-3
Glucose-dependent insulin secretion
Fasting insulin concentrations
First- and second-phase insulin secretion
Postprandial insulin secretion
Glucose-dependent glucagon secretion
Fasting glucagon concentrations
Postprandial glucagon concentrations
Gastric emptying
Food intake

14. The clinical importance of the small difference in A1C is uncertain.
In addition, it is unclear if insulin glargine was adequately titrated, since
only 21 percent of patients taking insulin glargine had fasting glucose
levels within the goal range (72 to 99 mg/dL).
Exenatide QW vs Basal Insulin

15. Long term efficacy vs basal Insulin:
Significant Weight Loss* with Exenatide QW vs Weight
Gain with Insulin Glargine
+2.01±0.28 kg
-2.49±0.28 kg
= -4.51±0.37 kg
95% CI [-5.23, -3.79]
P<0.001†
ITT population
-4
-3
-2
-1
0
1
2
3
0 8 18 26 36 48 60 72 84 96 108 120 132 144 156
Exenatide QW, N=233 Insulin Glargine, N=223
Time (wks)
BodyWeight(kg)
In the insulin glargine arm, from a starting daily insulin dose of 10 IU/day, mean dose increased to 31 IU/day at 26 weeks and 39 IU/day at 3 years1-3
1. Diamant M, et al. Lancet 2010;375:2234–43; 2. Diamant M, et al. Diabetes care 2012;35:683-689 ; 3. Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464–73;
DURATION-3: Treatment difference of 4.5 kg vs titrated insulin glargine3
*BYDUREON is not indicated for the management of obesity and weight change was a secondary endpoint in clinical trials4

16. The exposure-adjusted rate of hypoglycemia in the Exenatide QW group compared with IG was 0.3 vs 0.9/year
There were no events of major hypoglycemia resulting in loss of consciousness or seizure in the study
12
30
40
63
0
10
20
30
40
50
60
70
Treatment +
metformin
Treatment +
metformin + SU
Background oral antihyperglycaemic
medication
P<0.001
P<0.001
Exenatide QW, n=233 Insulin glargine, n=223
DURATION-3: Hypoglycemia rates
%ofpatientsreporting≥1
minorhypoglycemic
episode
Trautmann M, et al. Presented at the 73rd Scientific Sessions of the American Diabetes Association, Chicago, IL, USA, June 21-25, 2013; 067-OR

17. EXENATIDE vs other GLP1

18. Changes in A1C values with GLP-1 RAs head-to-
head clinical studies
Trujillo et al. Ther Adv Endocrinol Metab 2015, Vol. 6(1) 19–28

19. In the DURATION clinical trials, Exenatide QW
demonstrated HbA1c reductions of –1.3% to –1.9%
Data from 24–30 Weeks; *p<0.05 versus both; †p<0.01; ‡p<0.0001; §p=0.02; ||p=0.017; ¶ITT
population;
#Modified ITT population.
1. Bergenstal RM, et al. Lancet 2010;376:431–9; 2. Drucker DJ, et al. Lancet 2008;372:1240–50;
3. Blevins T, et al. J Clin Endocrin Metab 2011;96:1301–10; 4. Buse JB, et al. Lancet 2013;381:117–24;
5. Diamant M, et al. Lancet 2010;375:2234–43.
Exenatide BID¶2
n=295
30 weeks
Exenatide BID¶3
n=252
24 weeks
Baseline (%)
Sitagliptin (100 mg QD) or
Pioglitazone (45 mg QD)¶1
n=491
26 weeks
Insulin glargine#5
n=448
26 weeks
Bydureon versus Liraglutide 1.8 mg¶4
n=911
26 weeks
Sitagliptin PioglitazoneExenatide QW LiraglutideExenatide BID Insulin glargine
–1.9%†
–1.5% –1.6%‡
–0.9%
LSmeanchangeinHbA1c(%)
0
–0.5
–1.0
–1.5
–2.0
–1.5%*
–1.2%
–0.9%
8.3 8.3 8.5 8.48.6 8.5 8.5 8.3 8.3
–1.5% –1.5%||
–1.3%–1.3%§
8.5 8.4

20. Retrospective cohort study used the Quintiles Electronic Medical Record (EMR) database to evaluate the 6-month change in HbA1c for
patients initiating exenatide QW or liraglutide. Baseline HbA1c measures were from 75 days prior to 15 days after initiating exenatide QW or
liraglutide, with follow-up measures documented at 6 months (± 45 days). For exenatide QW and liraglutide respectively, mean (SD) age of
the main study cohort was 58.0 (11.0) and 58.1 (11.0) years, mean (SD) baseline HbA1c was 8.3% (1.7) and 8.4% (1.6).
**Adjusted for age, gender, race, baseline HbA1c, body mass index, number of other antidiabetes medication classes, Deyo-Charlson
Comorbidity Index, insurance type, region, hyperlipidemia, and hypertension.
Reference: Adapted from Saunders et al. Presented at the 74th Scientific Sessions of the American Diabetes Association, San Francisco,
California, June 13–17, 2014: Abstract 1192-P
Mean HbA1C reductions
Exenatide QW vs Liraglutide
ADA 2014:Real World Study

21. Changes in weight with GLP-1 RAs head-to-head
clinical studies
p-values are for statistical superiority (unless noted for noninferiority); *p = not significant, †p = 0.0005, ‡p-value not reported
for weight difference of 1.02 kg (95% confidence interval 0.456–1.581), §p < 0.0001, ¶ p < 0.001 versus dulaglutide 0.75 mg,
**p = not significant between dulaglutide 1.5 mg versus exenatide bid, ‡‡p = 0.011.
Trujillo et al. Ther Adv Endocrinol Metab 2015, Vol. 6(1) 19–28

22. Henry R, et al. ADA Scientific Sessions 2014; Sat., June 14 11:30 – 1:30PM, Poster 964-P
Significant weight reduction from baseline maintained
through 6 years treatment with Exenatide QW

23. Buse JB et al. Lancet. 2013;381:117-124.
Less than half the nausea rates vs daily GLP-1 RA

24. Set patients’ treatment expectations with BYDUREON
Patients may experience a
small raised bump within 2 to
4 weeks of injecting
BYDUREON
1. DeYoung et al. Diabetes Technol Ther. 2011;13(11):1145-1154. 2. BYDUREON Summary of Product Characteristics, February 2015.
• This is a localized inflammatory reaction to the microsphere polymer1
• Most individual nodules were asymptomatic, did not interfere with
treatment, and resolved on their own over 4 to 8 weeks2

25. Safety and tolerability of Exenatide QW
• Discontinuations due to AEs occurred less frequently with Exenatide QW than
with other GLP1RAs
• Less GI AEs, diminish over time
• Injection site related AEs more frequent with EQW than with other GLP1RAs
• No case of pancreatic cancer/ c-cell carcinoma/thyroid cancer
• Pancreatitis-rare
MacConell et al. Diabetes, Metabolic Syndrome and Obesity:
Targets and Therapy 2015:8 241–253
An integrated analysis of 4,328 patients with type 2 diabetes

26. ADHERENCE TO GLP1 THERAPY IN T2DM
After adjusting for confounders, patients initiating Exenatide QW had significantly
higher odds of adherence versus those initiating Exenatide BID, liraglutide 1.2 mg, and
liraglutide 1.8 mg (P≤0.01)
Adapted from Johnston S, et al. ADA Scientific Sessions 2014; Abstract 2379 – Publication Only

27. Exenatide QW Dosing and Administration
Single-Dose Tray
• Contains all components needed
for self administration
• Step-by-step guide included in
every carton
Subcutaneous injection once
every 7 days
Any time of day, independent
of meals
Fixed dose with no titration needed
The patient should read the Exenatide QW Medication Guide and the Instructions for Use
before starting Exenatide QW therapy and review them each time the prescription is filled.
Single-Dose Tray
Each monthly carton
contains
4 Single-Dose Trays