bydureon ® (exenatide once weekly) clinical data slide deck developed with the guidance and...

Bydureon® (exenatide once weekly) clinical data slide deck

Developed with the guidance and approval of an independent international editorial committee

Date of approval: March 2015 | Date of expiry: March 2016Approval code: 675,057.01

Prescribing information can be found at the end of this slide deck.

Content guide

• This deck comprises a number of slides, arranged in story order. You may find that some slides are not relevant to your audience. Please hide these as you feel necessary

• All graphs have been created in PowerPoint to enable easy amends and translation

• HbA1c values and appropriate graphs include both DCCT (%) and IFFC (mmol/mol) units. Please delete where not appropriate for your market

DCCT, Diabetes Control and Complications Trial; IFFC, International Federation of Clinical Chemistry and Laboratory Medicine.

Executive summary

• This slide deck covers the following topics and contains notes to provide further information on:1. Introduction to Bydureon, microsphere technology and the steady-state principle

2. Overview of the Bydureon clinical trial programme (DURATION studies)

3. Data from the Bydureon DURATION-1, -2 and -3 studies• Overview of study design (primary analysis and extension periods)

• Detailed data from long-term extension studies

4. Cardiovascular data from Bydureon studies

5. Bydureon safety and tolerability profiles

6. Dosing, administration and tips for initiating patients on Bydureon

Introduction to Bydureon (exenatide once-weekly)

When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.

GLP-1, glucagon-like peptide-1; SU, sulphonylurea; TZD, thiazolidinedione.Bydureon. Summary of product characteristics, 2014.

About Bydureon

• Bydureon is a GLP-1 receptor agonist, and the first once-weekly treatment for Type 2 diabetes

– EU marketing authorisation received in June 2006

• Bydureon provides continuous glycaemic control in a single weekly injection

• Bydureon is indicated for the treatment of Type 2 diabetes in combination with:

– Metformin

– SU

– TZD

– Metformin + SU

– Metformin + TZD

Bydureon’s patented microsphere technology enables once-weekly dosing

• Proven microsphere technology provides a continuous level of exenatide1

– Microspheres consist of a biodegradable polymer that dissipates into CO2 and water1

– The technology is also used in other extended-release products such as risperidone and naltrexone2,3

Further degradation and metabolism of microsphere polymer provide sustained

level of exenatide1

Microsphere degradation and continued release of

exenatide1

Individual microspheres aggregate and initial release of exenatide1

Subcutaneous injection of microsphere suspension of

exenatide1

Slide is animated

CO2, carbon dioxide.1. DeYoung MB, et al. Diabetes Technol Ther 2011;13:1145–54; 2. Risperdal Consta. Summary of product characteristics, 2013; 3. Vivitrol. Prescribing information. Alkermes, Inc, 2013.

Steady-state exenatide concentrations provide continuous glycaemic control with a single weekly injection

• With once-weekly injections of Bydureon, therapeutic concentrations of exenatide are reached in 2 weeks1,2

• Steady state is reached by 6–7 weeks1,2

– At steady state, there are minimal peak-to-trough fluctuations in exenatide levels

1. Bydureon. Summary of product characteristics, 2014; 2. Kim D, et al. Diabetes Care 2007;30:1487–93.

Time (weeks)

450

400

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Steady state is maintained with subsequent weekly doses

Slide is animated

Weekly Bydureon injection

Steady state achieved for continuous glycaemic control

Figure adapted from Kim D, et al. 2007, showing mean ± standard deviation.2

Bydureon clinical trial programme

Core design of DURATION trials

• DURATION: Diabetes Therapy Utilisation: Researching Changes in A1c, Weight, and Other Factors Through Intervention with Exenatide Once Weekly

• Primary endpoint: Change in HbA1c from baseline1–6

• Secondary endpoints included: Change in bodyweight, blood pressure and CV risk markers from baseline; safety and tolerability1–6

CV, cardiovascular.1. Drucker DJ, et al. Lancet 2008;372:1240–50; 2. Bergenstal RM, et al. Lancet 2010;376:431–9; 3. Diamant M, et al. Lancet 2010;375:2234–43; 4. Russell-Jones D, et al. Diabetes Care 2012;35:252–8; 5. Blevins T, et al. J Clin Endocrinol Metab 2011;96:1301–10; 6. Buse JB, et al. Lancet 2013;381:117–24.

Patients with:Type 2 diabetesHbA1c 7.1–11.0%

(54.1–96.7 mmol/mol)

Optional Bydureon extension

Bydureon 2 mg

Active comparator agent(s)

24–30 weeks

Bydureon is not indicated in Europe as monotherapy in patients uncontrolled on diet and exercise alone. 7

BID, twice daily; MET, metformin; PIO, pioglitazone; QD, once daily; SITA, sitagliptin; SU, sulphoylurea; TZD, thiazolidinediones.1. Drucker DJ, et al. Lancet 2008;372:1240–50; 2. Bergenstal RM, et al. Lancet 2010;376:431–9; 3. Diamant M, et al. Lancet 2010;375:2234–43; 4. Russell-Jones D, et al. Diabetes Care 2012;35:252–8; 5. Blevins T, et al. J Clin Endocrinol Metab 2011;96:1301–10; 6. Buse JB, et al. Lancet 2013;381:117–24; 7. Bydureon. Summary of product characteristics, 2014.

Overview of DURATION trials

• Data from DURATION-1, -2 and -3 are shown here as the primary studies included in the Bydureon summary of product characteristics7

– When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia7

Trial Comparator Background Subjects In EU label

DURATION-11 Exenatide BIDOpen label

Drug naïve, MET, SU, TZD, or two of these agents

295

DURATION-22 SITA (100 mg QD) or PIO (45 mg QD)Double-blind

MET 491

DURATION-33 Insulin glargineOpen label

MET ± SU 456

DURATION-44 MET (2000 mg QD) or PIO (45 mg QD) or

SITA (100 mg QD)Double-blind

Drug naïve 820

DURATION-55 Exenatide BIDOpen label

Drug naïve, MET, SU, TZD, or a combination of these agents

252

DURATION-66 Liraglutide (1.8 mg)Open label

MET, SU, TZD, or a combination of these agents

911

Slide is animated

DURATION-1

DURATION-1: Study details

BID, twice daily; FPG, fasting plasma glucose; ITT, intent-to-treat; PPG, postprandial glucose; SU, sulphonylurea; TZD, thiazolidinedione.Drucker DJ, et al. Lancet 2008;372:1240–50.

DURATION-1: Primary analysis

Study details N=295 (ITT population)Randomised, active-controlled, open-label, non-inferiority study

Study length 30 weeks

Background therapy None (as initial therapy) or treatment with metformin, a SU, a TZD or any combination of these agents

Comparator to Bydureon

Exenatide BID

Primary endpoint HbA1c change from baseline at Week 30

Secondary endpoints Safety and tolerability; analysis of FPG, PPG, bodyweight, fasting glucagon, fasting lipids, blood pressure, exenatide pharmacokinetics, paracetamol absorption

Publication type Peer-reviewed journal articleWhen Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.

DURATION-1: Study details (continued)

DURATION-1: 52-week extension study

Study details N=258 (entering open-ended assessment period)Extension study after completing a 30-week randomised, active-controlled, open-label, non-inferiority study

Study length 22 weeks after completion of the 30-week primary study



Exenatide BID Bydureon at Week 30

Outcomes Glucose control during the transition from exenatide BID to Bydureon; safety and tolerability; efficacy of Bydureon at Week 52

Publication type Peer-reviewed journal article

BID, twice daily; SU, sulphonylurea; TZD, thiazolidinedione.Buse JB, et al. Diabetes Care 2010;33:1255–61.



BID, twice daily; FPG, fasting plasma glucose; SBP, systolic blood pressure; SU, sulphonylurea; TZD, thiazolidinedione.MacConell L, et al. Diabetes Metab Syndr Obes 2013;6:31–41.

DURATION-1: 3-year extension study

Study details N=258 (entering open-ended assessment period)Extension study after completing a 30-week randomised, active-controlled, open-label, non-inferiority study

Study length 3-year extension (switch study)



No comparator; pooled population included patients initated on Bydureon and those initiated on exenatide BID and switching to Bydureon at Week 30

Study endpoints Change in HbA1c, FPG, weight, lipid profile and SBP

Publication type Peer-reviewed publication



BID, twice daily; FPG, fasting plasma glucose; SBP, systolic blood pressure; SU, sulphonylurea; TZD, thiazolidinedione.Henry RH, et al. Poster presented at ADA 2014. 964-P.


Study details N=258 (entering open-ended assessment period; completer population n=127)Extension study after completing a 30-week randomised, active-controlled, open-label, non-inferiority study

Study length 6-year extension (switch study)



No comparator; pooled population included patients initiated on Bydureon and those initiated on exenatide BID and switching to Bydureon at Week 30

Study endpoints Change in HbA1c, FPG, weight, lipid profile and SBP

Publication type Congress abstract and poster presentation


DURATION-1: Reduced HbA1c with Bydureon versus exenatide BID over 1 year1

• At the primary endpoint of 30 weeks, HbA1c reductions from baseline were –1.9% (–20.8 mmol/mol) with Bydureon and –1.5% (–16.4 mmol/mol) with exenatide BID (p=0.0023)2

• At 1 year, patients receiving Bydureon maintained HbA1c reductions of –2.0% (–21.9 mmol/mol), regardless of whether they started on Bydureon or switched to Bydureon at 30 weeks1

– 71% of all patients achieved HbA1c <7% with Bydureon, irrespective of treatment at initiation

BID, twice daily; BL, baseline.1. Buse JB, et al. Diabetes Care 2010;33:1255–61; 2. Drucker DJ, et al. Lancet 2008;372:1240–50.

Bydureon BL=8.3% (67.2 mmol/mol)

Exenatide BID Bydureon BL=8.2% (66.1 mmol/mol)

60 524844403633302622181410–2.5

–2.0

–1.5

–1.0

–0.5

0.0

Time (weeks)

Ch

an

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in

Hb

A1c

(%

)

** * * * * * *

All subjects received Bydureon

–2.0% (21.9 mmol/mol)

–2.0%(21.9 mmol/mol)

Change from BL:

–25

–20

–15

–10

–5

0 Ch

an

ge

in H

bA

1c (mm

ol/m

ol)

Figure adapted from Buse JB, et al. 2010, showing least-squares mean ± standard error.1 *p<0.05 versus exenatide BID.

DURATION-1: Reduced HbA1c with Bydureon sustained over 6 years

• HbA1c reductions were sustained over 6 years with Bydureon (mean change in HbA1c from baseline –1.6% [95% CI, –1.9 to –1.4] [–17.5 mmol/mol])3

• 45% of all patients achieved HbA1c <7% with Bydureon, irrespective of treatment at initiation

BID, twice daily; BL, baseline; CI, confidence interval.1. Drucker DJ, et al. Lancet 2008;372:1240–50; 2. MacConell L, et al. Diabetes Metab Syndr Obes 2013;6:31–41; 3. Henry RH, et al. Poster presented at ADA 2014. 964-P.

6 years3

(n=127)3 years2

(n=194)30 weeks1

(n=148)

– 2.0

–1.5

–1.0

–0.5

0.0

Ch

an

ge

in

Hb

A1c

(%

)

–1.6%(17.5

mmol/mol)

–1.6%(–17.5

mmol/mol)

BL=8.2%(66.1

mmol/mol)

–1.6%(–17.5

mmol/mol)

BL=8.2%(66.1

mmol/mol)

–1.9%(–20.8

mmol/mol)

BL=8.3%(67.2

mmol/mol)

–20

–15

–10

–5

0 Ch

an

ge

in H

bA

1c (mm

ol/m

ol)

Randomised to Bydureon (evaluable population)

Pooled population (all Bydureon completers)

Figure adapted from Drucker DJ, et al. 2008,1 MacConell L, et al. 2013,2 and Henry RH, et al. 2014.3

DURATION-1: Weight reductions with Bydureon versus exenatide BID over 1 year*

• Powerful HbA1c reductions with Bydureon were accompanied by weight reductions of 4.1–4.5 kg at 1 year1

*Bydureon is not indicated for the treatment of obesity and weight change was a secondary endpoint in clinical trials. 3

BID, twice daily; BL, baseline.1. Buse JB, et al. Diabetes Care 2010;33:1255–61; 2. MacConell L, et al. Presented at EASD 2013. Abstract 980; 3. Bydureon. Summary of product characteristics, 2014.

60 5248444036302622181410–5

–4

–3

–2

–1

0

Time (weeks)

Ch

an

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in

bo

dy

we

igh

t (k

g)

All subjects received Bydureon

–4.1 kg

–4.5 kg

Change from BL:

BydureonBL=103 kg

Exenatide BID Bydureon BL=102 kg

Figure adapted from Buse JB, et al. 2010, showing least squares mean ± standard error.1

DURATION-1: Weight reductions with Bydureon sustained over 6 years*

• Weight reductions with Bydureon were sustained over 6 years (mean reductions from baseline –4.3 kg [95% CI, –6.0 to –2.6])

*Bydureon is not indicated for the management of obesity and weight change was a secondary endpoint in clinical trials. 4

BID, twice daily; BL, baseline.1. Drucker DJ, et al. Lancet 2008;372:1240–50; 2. MacConell L, et al. Diabetes Metab Syndr Obes 2013;6:31–41; 3. Henry RH, et al. Poster presented at ADA 2014. 964-P; 4. Bydureon. Summary of product characteristics, 2014.

6 years3

(n=127)3 years2

(n=194)30 weeks1

(n=148)

–4

–3

–2

–1

0

Ch

an

ge

in

bo

dy

we

igh

t (k

g)

–1.6%(17.5

mmol/mol)

–2.3 kg

BL=101 kg

–4.3 kg

BL=101 kg

–4.0 kg

BL=102 kg

Randomised to Bydureon (evaluable population)

Pooled population (all Bydureon completers)

–5

Figures adapted from Drucker DJ, et al. 2008,1 MacConell L, et al. 2013,2 and Henry RH, et al. 2014.3

DURATION-2


CV, cardiovascular; FPG, fasting plasma glucose; HRQoL, health-related quality of life; ITT, intent-to-treat; SMBG, self-monitored blood glucose; QD, once daily.Bergenstal RM, et al. Lancet 2010;376:431–9.


Study details N=491 (ITT population)Randomised, double-blind, double-dummy, active-controlled superiority trial


Background therapy Metformin

Comparators to Bydureon

Sitagliptin 100 mg QDPioglitazone 45 mg QD

Primary endpoint Change in HbA1c from baseline at Week 26

Secondary endpoints Proportion of patients achieving HbA1c ≤6.5% (≤47.5 mmol/mol) or ≤7.0% (≤53.0 mmol/mol); FPG; six-point SMBG profile; bodyweight; fasting lipid profile; fasting insulin profile; blood pressure; CV risk markers; patient-reported HRQoL; safety and tolerability



CV, cardiovascular; FPG, fasting plasma glucose; QD, once daily.Wysham C, et al. Diabet Med 2011;28:705–14.

DURATION-2: 52-week extension study

Study details N=364 (entering extension study)Extension study after completing a 26-week randomised, double-blind, double-dummy, superiority trial

Study length 26 weeks with a 26-week extension (switch study)

Background therapy Metformin

Comparators to Bydureon

Patients initiated on sitagliptin 100 mg QD Bydureon at Week 26Patients initiated on pioglitazone 45 mg QD Bydureon at Week 26

Outcomes Change from baseline at Weeks 26 and 52 and from Week 26 to Week 52 in: HbA1c; patients achieving HbA1c <7.0% (<53.0 mmol/mol) and ≤6.5% (≤47.5 mmol/mol); FPG; bodyweight; fasting lipids; fasting insulin; blood pressure; CV risk markers; safety and tolerability


DURATION-2: Reduced HbA1c with Bydureon versus sitagliptin and pioglitazone

• At the primary endpoint of 26 weeks, HbA1c changes from baseline were –1.5% (–16.4 mmol/mol) with Bydureon, –0.9% (–9.8 mmol/mol) with sitagliptin and –1.2% (–13.1 mmol/mol) with pioglitazone (p<0.05 for Bydureon vs both comparators)1

• Significant HbA1c reductions with Bydureon were achieved at 1 year, regardless of initial therapy2

BL, baseline; CI, confidence interval.1. Bergenstal RM, et al. Lancet 2010;376:431–9; 2. Wysham C, et al. Diabet Med 2011;28:705–14.

Bydureon, BL=8.6% (70.5 mmol/mol) Sitagliptin Bydureon, BL=8.5% (69.4 mmol/mol)Pioglitazone Bydureon, BL=8.5% (69.4 mmol/mol)

–0.31% (95 % CI, –0.50 to –0.13)* (–3.4 mmol/mol)Change from Week 26 to Week 52:

0.06% (95 % CI, –0.13 to 0.25) (0.7 mmol/mol)

–0.10% (95 % CI, –0.29 to 0.09) (–1.1 mmol/mol)

60 52464034302622181410–2.0

–0.5

0.0

Time (weeks)

Ch

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A1c

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–1.5

–1.0

–20

–15

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Ch

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bA

1c from

b

as

elin

e (m

mo

l/mo

l)

Graph adapted from Wysham C, et al. 2011, showing data for the evaluable population as least squares mean ± standard error.2 *p<0.05 versus Week 26.

DURATION-2: Weight change* with Bydureon versus sitagliptin and pioglitazone

• Patients treated with Bydureon achieved significant weight reductions at 26 weeks*1

– Individuals who switched to Bydureon from sitagliptin or pioglitazone at the end of the blinded period experienced further weight reductions2

*Bydureon is not indicated for the treatment of obesity and weight change was a secondary endpoint in clinical trials. 3

BL, baseline; CI, confidence interval.1. Bergenstal RM, et al. Lancet 2010;376:431–9; 2. Wysham C, et al. Diabet Med 2011;28:705–14; 3. Bydureon. Summary of product characteristics, 2014.

Blinded period

–1.1 kg (95% CI, –1.8 to –0.5)†

Change from Week 26:

0.7 kg (95 % CI, 0.1 to 1.4)†

–3.0 kg (95 % CI, –3.7 to –2.3)†

60 52464034302622181410–3

–2

0

2

3

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Time (weeks)

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1

4

Open-label period

Bydureon, BL=90 kgSitagliptin Bydureon, BL=86 kgPioglitazone Bydureon, BL=86 kg

Graph adapted from Wysham C, et al. 2011, showing data for the evaluable population (least squares mean ± standard error).2 †p<0.05 versus Week 26.

DURATION-3


AAT, alanine aminotransferase; ACR, albumin-to-creatinine ratio; CRP, C-reactive protein; FPG, fasting plasma glucose; HOMA, homeostasis model assessment; HRQoL, health-related quality of life; SMBG, self-monitored blood glucose; SU, sulphonylurea. Diamant M, et al. Lancet 2010;375:2234–43.


Study details N=456 (ITT population)Open-label, randomised, parallel-group study


Background therapy Metformin ± SU


Insulin glargine (starting dose: 10 IU/day)

Primary endpoint Change in HbA1c from baseline at Week 26

Secondary endpoints Patients achieving HbA1c <7.0% (<53.0 mmol/mol) and ≤6.5% (≤47.5 mmol/mol); FPG; SMBG; bodyweight; fasting plasma lipids; urinary ACR; CRP; HOMA β-cell function and insulin sensitivity; AAT; HRQoL; 1,5-anhydroglucitol; safety and tolerability




ACR, albumin-to-creatinine ratio; FPG, fasting plasma glucose; HOMA, homeostasis model assessment; SMBG, self-monitored blood glucose; SU, sulphonylurea; WHR, waist-to-hip ratio.Diamant M, et al. Diabetes Care 2012;35:683–9.

DURATION-3: Planned interim analysis at 84 weeks of open-ended extension study

Study details N=390 (entering extension study)Open-label, randomised, parallel-group study

Study length 26 weeks with open-ended extension study; interim analysis at 84 weeks



Insulin glargine (starting dose 10 IU/day; target glucose range, 4.0–5.5 mmol/L)

Key efficacy measure Change in HbA1c from baseline to study treatment endpoint

Secondary efficacy measures

Time to failure to maintain glycaemic control; patients achieving HbA1c <7.0% (<53.0 mmol/mol) and ≤6.5% (≤47.5 mmol/mol); bodyweight; FPG; SMBG, fasting serum lipids

Exploratory measures Urinary ACR; HOMA β-cell function; WHR; anti-exenatide antibody titre; safety and tolerability

Publication type Peer-reviewed journal articleWhen Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.


ACR, albumin-to-creatinine ratio; CRP, C-reactive protein; FPG, fasting plasma glucose; SMBG, self-monitored blood glucose; SU, sulphonylurea; WHR, waist-to-hip ratio.Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464–73.


Study details N=390 (entering extension study; completer population n=287)Open-label, randomised, parallel study

Study length 26 weeks with 3-year extension



Insulin glargine (starting dose 10 IU/day; target glucose range, 4.0–5.5 mmol/L)

Key efficacy measure Change in HbA1c from baseline to study treatment endpoint

Secondary measures Patients achieving HbA1c <7.0% (<53.0 mmol/mol) and ≤6.5% (≤47.5 mmol/mol); bodyweight; FPG; SMBG, fasting serum lipids; patient-reported outcomes; safety and tolerability

Exploratory measures Blood CRP concentrations; urinary ACR; WHR

Publication type Peer-reviewed publicationWhen Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.

• At the primary endpoint of 26 weeks, HbA1c reductions from baseline were –1.5% (–16.4 mmol/mol) with Bydureon and –1.3% (–14.2 mmol/mol) with insulin glargine (p=0.017)1

• Bydureon-treated patients experienced significantly greater HbA1c reductions at 3 years than those treated with insulin glargine2

DURATION-3: Reduced HbA1c with Bydureon versus basal insulin over 3 years

BL, baseline.1. . Diamant M, et al. Lancet 2010;375:2234–43; 2. Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464–73.

Graph adapted from Diamant M, et al. 2014, showing data for the modified intent-to-treat population as least squares mean ± standard error. 2 *p=0.03.

156144108847248 6036261800

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l)

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20

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70

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6

7

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40

30

Bydureon, BL=8.3% (67.2 mmol/mol; n=228) Insulin glargine, BL=8.3% (67.2 mmol/mol; n=220)

–1.01 ± 0.7% (–11.0 mmol/mol)*

–0.81 ± 0.07% (–8.9 mmol/mol)

Change from BL:

• Treatment with Bydureon resulted in significant weight reduction instead of weight gain with insulin glargine over 3 years1

DURATION-3: Weight change with Bydureon versus basal insulin over 3 years

BL, baseline.Bydureon is not indicated for the treatment of obesity and weight change was a secondary endpoint in clinical trials. 2

1. Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464–73; 2. Bydureon. Summary of product characteristics, 2014.

Time (weeks)

+2.01 ± 0.28 kg

–2.49 ± 0.28 kg*

15613284724836 60268

–4

–2

2

4

Ch

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t (k

g)

0

0

Bydureon, BL=91.2 kg (n=233)Insulin glargine, BL=90.6 kg (n=222)

Change from BL:

18 96 108 120 144

Graph adapted from Diamant M, et al. 2014, showing data for the modified intent-to-treat population as least squares mean ± standard error.1 *p<0.001.

DURATION-3: Individual associations between HbA1c and body weight with Bydureon versus insulin glargine at 26 weeks*1

Insulin glargine

Bydureon

79%

31%

4%

1%

16%

63%

Modified ITT population, N=448.

We

igh

t c

ha

ng

e f

rom

ba

se

lin

e (

kg

)

HbA1c (%) change from baseline

16

12

8

4

0

–4

–8

–12

–16–6 –4 –2 0 2 4 6

*Bydureon is not indicated for the management of obesity and weight change was a secondary endpoint in clinical trials. 2 1. Diamant M, et al. Lancet 2010;375:2234–43; Bydureon. Summary of product characteristics, 2014.

0%

5%

*Figure adapted from Diamant M, et al. Lancet 2010.1

DURATION-3: Incidence of minor hypoglycaemia versus insulin glargine

• Bydureon was associated with a lower rate of minor hypoglycaemia than insulin glargine at 84 weeks1

• The exposure-adjusted rate of overall hypoglycaemia at 3 years was three times higher with insulin glargine (0.9 events/patient/year) than with Bydureon (0.3 events/patient/year)2

– SUs are associated with a higher risk of hypoglycaemia; when Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia3

SU, sulphonylurea.1. Diamant M, et al. Diabetes Care 2012;35:683–9; 2. Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464–73; 3. Bydureon. Summary of product characteristics, 2014.

Metformin background

Pa

tie

nts

re

po

rtin

g m

ino

r h

yp

og

lyc

ae

mia

(%

)

32%

n=51

Bydureon (n= 233)Insulin glargine (n=223)

54%

n=36

Metformin + SU background

8%n=13

* 24%

n=17

*

0

50

70

2030

60

40

10

80

10090

Graph adapted from Diamant et al. Diabetes Care 2012.1 *p<0.001. Minor hypoglycaemia was defined any time a paitent felt that he or she had a sign or symptom of hypoglycaemia that was associated with concurrent blood glucose <3.0 mmol/L and that was either self-treated by the patient or resolved independently. 1 Three patients (one Bydureon + metformin, one insulin glargine + metformin and insulin glargine + metformin and SU) had an episode of hypoglycaemia requiring the assistance of another person, but not involving loss or severe impairment of consciousness, during the first 26 weeks. 1

Change in CV risk markers with Bydureon

Evidence from DURATION-1

Bydureon is not indicated for the management of blood pressure or cholesterol.1

CV, cardiovascular.1. Bydureon. Summary of product characteristics, 2014.

DURATION-1: Changes in blood pressure over 1 year with Bydureon

• Over 1 year in the DURATION-1 study, improvements from baseline in blood pressure were seen with Bydureon treatment1,2

• At 1 year, 50% of patients with a high baseline SBP (≥130 mmHg) achieved a normal SBP2


DBP, diastolic blood pressure; SBP, systolic blood pressure.1. Drucker DJ, et al. Lancet 2008;372:1240–50; 2. Buse JB, et al. Diabetes Care 2010;33:1255–61; 3. Bydureon. Summary of product characteristics, 2014.

0

–1

–2

–3

–4

–5

–6Ch

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ge

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BP

(m

mH

g)

SBP

Week 301

n=148

–4.7mmHg

–6.2mmHg

–1.7mmHg

–2.8mmHg

Year 12

n=148

DBP

Week 301

n=148Year 12

n=148Baseline 128 129 78 78

–7

Figure adapted from Drucker DJ, et al. 20081 and Buse JB, et al. 2010,2 showing ITT population of patients randomised to Bydureon (n=148).

• Over 1 year in the DURATION-1 study, improvements from baseline in plasma lipids were observed with Bydureon treatment1,2

• Improvements were maintained for up to 6 years3

DURATION-1: Changes in lipid profile at 1 year with Bydureon


BL, baseline; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NR, not reported; TG, triglycerides.1. Drucker DJ, et al. Lancet 2008;372:1240–50; 2. Buse JB, et al. Diabetes Care 2010;33:1255–61; 3. Henry RH, et al. Poster presented at ADA 2014. 964-P; 4. Bydureon. Summary of product characteristics, 2014.

0.0

–0.1

–0.2

–0.3

–0.4

Ch

ang

e fr

om

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L (

mm

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)

Total cholesterolWeek 301

–0.31mmol/L

–0.25mmol/L

Year 12

BL=4.49 BL=4.40

0.1

0.0

–0.1

Ch

ang

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om

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L (

mm

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)

HDL-C

Week 301

–0.02mmol/L

+0.02mmol/L

Year 12

BL=1.14

BL=1.14

0.1

0.0

–0.1

–0.2

–0.3

Ch

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LDL-C

Week 301

–0.13mmol/L

–0.09 mmol/L

Year 12

BL=2.37 BL=2.30

0

–5

–10

–15C

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ge

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m

BL

(%

)

Triglycerides

Week 301

–15%

–15%

Year 12

BL=1.88 BL=1.82

Figures adapted from Drucker DJ, et al. 20081 and Buse JB, et al. 2010,2 showing ITT population of patients randomised to Bydureon (n=148).

Bydureon safety and tolerability profile

Bydureon: Summary of safety and tolerability profile

• As with other GLP-1 receptor agonists,1–4 the most frequent adverse drug reactions (≥5% of patients treated with Bydureon) were mainly gastrointestinal-related (nausea, vomiting, diarrhoea and constipation)

• In addition, injection-site reactions (pruritus, nodules, erythema), hypoglycaemia (with a SU) and headache occurred1

• Most adverse reactions associated with Bydureon were mild to moderate in intensity1

• There have been rare, spontaneously reported events of acute pancreatitis and renal failure. If pancreatitis is suspected, Bydureon should be discontinued1

Data source comprises two placebo-controlled studies (10 and 15 weeks) and three studies of Bydureon versus exenatide BID (30-week study), sitagliptin and pioglitazone (26-week study) or insulin glargine (26-week study). Background therapies included diet and exercise, metformin, a SU, a TZD or a combination of oral antidiabetic agents. BID, twice daily; SU, sulphonylurea; TZD, thiazolidinedione.1. Bydureon. Summary of product characteristics, 2014; 2. Byetta. Summary of product characteristics, 2014; Victoza. Summary of product characteristics, 2014; 4. Lyxumia. Summary of product characteristics, 2014.

Very common and common adverse reactions reported with Bydureon in clinical trials

System organ class/adverse reaction terms

Frequency of occurrence†

Very common (≥1/10) Common (≥1/100 to <1/10)

Metabolism and nutrition disorders Hypoglycaemia (with a SU)‡ Decreased appetite‡

Nervous system disorders Headache‡

Dizziness‡

Gastrointestinal disorders Nausea‡

Vomiting‡ Diarrhoea‡ Constipation

Dyspepsia‡

Abdominal pain‡

Gastroesophageal reflux disease‡

Abdominal distension‡

EructationFlatulence‡

Skin and subcutaneous tissue disorders Hyperhidrosis‡

General disorders and administration site conditions

Injection-site pruritus Fatigue‡

Injection-site erythemaInjection-site rashSomnolence

BID, twice daily; SU, sulphonylurea; TZD, thiazolidinedione.Bydureon. Summary of product characteristics, 2014.

• Most adverse reactions associated with BYDUREON were mild to moderate in intensity and only infrequently* led to discontinuation

• There have been rare, spontaneously reported events of acute pancreatitis and renal failure. If pancreatitis is suspected, Bydureon should be discontinued

*The incidence of withdrawal due to adverse events in Bydureon-treated patients during the 30-week controlled trial was 6%. †Rate based on Bydureon clinical trial data (N=592 total; n=135 patients on SU) When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia. ‡Reactions were in the same frequency grouping in the exenatide BID group. Data source comprises two placebo-controlled studies (10 and 15 weeks) and three studies of Bydureon versus exenatide BID (30-week study), sitagliptin and pioglitazone (26-week study) or insulin glargine (26-week study). Background therapies included diet and exercise, metformin, a SU, a TZD or a combination of oral antidiabetic agents.

Very common and common adverse reactions observed from clinical trial experience that were not observed with Bydureon at an incidence of ≥1%

System organ class/adverse reaction terms

Frequency of occurrence*

Very common (≥1/10) Common (≥1/100 to <1/10)

Skin and subcutaneous tissue disorders Hyperhidrosis

General disorders and administration site conditions

AstheniaFeeling jittery

BID, twice daily; SU, sulphonylurea; TZD, thiazolidinedione.Bydureon. Summary of product characteristics, 2014.

*Rate based on Bydureon clinical trial data (N=592 total; n=135 patients on SU).Data source comprises two placebo-controlled studies (10 and 15 weeks) and three studies of Bydureon versus exenatide BID (30-week study), sitagliptin and pioglitazone (26-week study) or insulin glargine (26-week study). Background therapies included diet and exercise, metformin, a SU, a TZD or a combination of oral antidiabetic agents. When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.

Handling nausea that may occur with Bydureon treatment

• Nausea is a frequent side effect with all GLP-1 receptor agonists1–4

• <1% of patients discontinued Bydureon due to nausea1

• Most episodes of nausea were mild to moderate and decreased over time1,5

• In a 52-week trial, even when patients experienced nausea, it did not affect their reported level of treatment satisfaction with Bydureon6

GLP-1, glucagon-like peptide-1.1. Bydureon. Summary of product characteristics, 2014; 2. Byetta. Summary of product characteristics 2014 3. Victoza. Summary of product characteristics, 2014; 4. Lyxumia. Summary of product characteristics, 2014; 5. Maggs D, et al. Presented at EASD 2012. Presentation #4; 6. Best JH, et al. Diabet Med 2009;26:722–8.

Inc

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a

(%)

0

100

40

60

80

20

0–3030–60

60–9090–120

120–150

150–180

180–212Weeks

Figure adapted from Maggs D, et al. 2012.5

Handling injection-site reactions that may occur with Bydureon treatment

Injection-site reactions versus bumps

• Injection-site reactions associated with symptoms were categorised as adverse events (erythema, pruritus, rash)

• Occurred in 16% of patients in Phase III studies

• Mostly mild to moderate• Usually did not lead to withdrawal

from studies

Injection-site bumps

• Small, raised nodules that very frequently occur at the injection site– These are consistent with known

properties of poly (D,L-lactide co-glycolide) polymer microsphere technology

• Bumps are normally harmless and resolve over 4–8 weeks

Bydureon. Summary of product characteristics, 2014.

Size of bump

Contraindications and special warnings and precautions

ContraindicationsHypersensitivity to the active substance or to any of the excipients.

Warnings and precautionsNot to be used in patients with Type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Bydureon must not be administered by intravenous or intramuscular injection.

• Renal impairment Rare, spontaneously reported events of altered renal function with exenatide, including increase serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring haemodialysis. Some occurred in patients experiencing events that may affect hydration and/or receiving medicinal products known to affect renal function/hydration status, including angiotensin converting enzyme inhibitors, angiotensin-II antagonists, non-steroidal anti-inflammatory medicinal products and diuretics. Reversibility observed with supportive treatment and discontinuation of potentially causative medicinal products, including exenatide.

No dose adjustment required for patients with mild renal impairment (CrCl 50–80 mL/min). Very limited experience in moderate renal impairment (CrCl 30–50 mL/min). Not recommended in patients with moderate renal impairment, severe renal impairment (CrCl <30 mL/min) or end-stage renal disease.

• Severe gastrointestinal diseaseNot recommended.

Please see the Bydureon summary of product characteristics for full safety information.

CrCl, creatinine clearance.Bydureon. Summary of product characteristics, 2014.

Contraindications and special warnings and precautions (continued)

• Acute pancreatitisRare, spontaneously reported events of acute pancreatitis. Inform patients of the characteristic symptom of acute pancreatitis: Persistent, severe abdominal pain. Resolution of pancreatitis has been observed with supportive treatment, but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis suspected, discontinue use of Bydureon and other potentially suspect medicinal products. Do not resume Bydureon after pancreatitis has been diagnosed.

• Concomitant medicinal productsConcurrent use of Bydureon with insulin, meglitinides, alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors or other GLP-1 receptor agonists has not been studied. The concurrent use of Bydureon and exenatide BID has not been studied and is not recommended.

• Weight lossRapid weight loss at a rate of >1.5 kg per week has been reported with exenatide, which may have harmful consequences.

• Discontinuation of treatmentThe effect of Bydureon may continue as plasma levels of exenatide decline over 10 weeks. Choice of other medicinal products and dose selection should be considered accordingly until exenatide levels decline.


BID, twice daily; GLP-1, glucagon-like peptide-1.Bydureon. Summary of product characteristics, 2014.

Drug interactions

No dose adjustment required for medicinal products sensitive to delayed gastric emptying.

• Warfarin and cumarol derivativesIncreased INR reported during concomitant use of warfarin and exenatide. INR should be monitored during initiation of Bydureon.

• HMG CoA reductase inhibitorsConcomitant use with exenatide was not associated with consistent changes in lipid profiles. Lipid profiles should be monitored as appropriate.


AUC, area under curve; BID, twice daily; HMG, hydroxy methyl glutaryl coenzyme A; INR, international normalised ratio.Bydureon. Summary of product characteristics, 2014.

Anti-exenatide antibodies

• Patients may develop antibodies to exenatide following treatment with Bydureon– Consistent with the potentially

immunogenic properties of protein and peptide pharmaceuticals1

– In clinical studies of Bydureon, approximately 45% of patients had low-titre antibodies at the study endpoint1

– Antibody titres usually diminish over time1

• Four clinical trials showing clinically relevant HbA1c reduction regardless of antibody status2

• A small proportion of patients (2.6%) had higher titres and showed no glycaemic improvement1

1. Bydureon. Summary of product characteristics, 2014; 2. Fineman MS, et al. Diabetes Obes Metab 2012;14:546–54.

–2.0

–0.5

0.0

Ch

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Hb

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–1.5

–1.0

–1.6%(–15.5

mmol/mol)

–1.3%(–14.2

mmol/mol)

Antibody-negative patients

Antibody-positive patients

Reduction in mean HbA1c by antibody status2

–20

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Bydureon dosing, administration and initiation

Bydureon dosing

• Bydureon comes in a convenient single-dose kit that contains everything patients need to prepare and deliver their once-weekly injection– Injection can be administered at any

time of the day, independently of meals

– Fixed dose with no titration required– Patients can change their day of

weekly dosing as long as doses are 1 day apart*

*If a dose is missed, it should be administered as soon as practical. Thereafter, patients can resume their once-weekly dosing schedule. The use of Bydureon does not require additional self-monitoring of blood glucose.Bydureon. Summary of product characteristics, 2014.

CONNECT

Connect the parts securely before mixing

SHAKE

Shake vigorously to mix the

medicine with the liquid

INJECT

Attach the needle, line up

the plunger with the dose line,

and inject

Bydureon device: Overview of the Connect, Shake, Inject process

• Contains an overview of the injection device– Straightforward dosing: Connect, Shake, Inject

– Remember: Patients should follow all of the steps in the instructions for the user that comes with the single-dose kit

Bydureon. Summary of product characteristics, 2014.

The Bydureon usability study

• A usability study of 102 individuals with Type 2 diabetes found that 88% of patients were able to prepare and deliver a dummy dose of Bydureon

Adapted from Lorenzi G, et al. Clin Diabetes 2010;28:157–62.

Subjects who succeeded in preparing and delivering a dose of Bydureon

72.6%(n=74)

Without assistance

With use of customer support helpline

15.7%(n=16)

11.8%(n=12)

Did not complete

Questionnaire responses to ‘If I only had the instructions for use, I could

use the single-dose kit at home’

69%(n=70)

22%(n=22)

7%(n=7)

2%(n=2) Strongly

agreeAgree

Neutral

Disagree/strongly disagree

FPG, fasting plasma glucose; HCP, healthcare professional; PPG, postprandial glucose.1. Bydureon. Summary of product characteristics, 2014; 2. Blevins T, et al. J Clin Endocrinol Metab 2011;96:1301–10; 3. Drucker DJ, et al. Lancet 2008;372:1240–50.

Expectation setting: Benefits

• To maximise adherence, a care plan should be agreed with the individual patient, including setting of expectations by the HCP, upon initiation of treatment

• Explain to patients that, due to its unique once-weekly formulation, they need to give Bydureon time to work

When you may see an effect Changes patients may notice

After four doses1,2 • FPG improvements• PPG improvements

After six or seven doses1,3 • HbA1c reductions

Over time1 • Feeling less hungry and eating less• Most patients will experience weight

reduction*

*Bydureon is not indicated for the management of obesity and weight change was a secondary endpoint in clinical trials. 1

Once-weekly Bydureon: Continuous glycaemic control for your patients

• Bydureon provides powerful efficacy with HbA1c reductions, sustained for up to 6 years1

• Potential for sustained weight reduction over 6 years* and low risk of hypoglycaemia†1,2

• Withdrawal rate of <1% due to nausea and vomiting2

• The most frequent adverse reactions (≥5% of Bydureon patients) were mainly gastrointestinal related (nausea, vomiting, diarrhoea and constipation)2

– In addition, injection-site reactions (pruritus, nodules, erythema) were observed

• Straightforward administration that patients can manage in a once-weekly injection2,3

*Bydureon is not indicated for obesity and weight change was a secondary endpoint in clinical trials. 2 †SUs are associated with an increased risk of hypoglycaemia. When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.2

1. Henry RH, et al. Poster presented at ADA 2014. 964-P; 2. Bydureon. Summary of product characteristics, 2014; 3. Lorenzi G, et al. Clin Diabetes 2010;28:157–62.

This information is consistent with the UK marketing authorisation. Please refer to your local prescribing information for full details.

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