1version 1.3 dr mohan k rao md fellowship in diabetes & endocrinology (utsw medical center,...

1Version 1.3

Dr Mohan K Rao MDFellowship in diabetes &

Endocrinology(UTSW Medical Center, Dallas, USA)

Consultant endocrinologistSagar Center for Diabetes

Sagar Hospitals

India: World Diabetic Capital

Country/Territory 2010 Millions Country/Territory 2030 Millions

1 India 50.8

1 India 87

2 China 43.2 2 China 62.6

3 USA 26.8 3 USA 36

4 Russian federation 9.6 4 Pakistan 13.8

5 Brazil 7.6 5 Brazil 12.7

6 Germany 7.5 6 Indonesia 12

7 Pakistan 7.1 7 Mexico 11.9

8 Japan 7.1 8 Bangladesh 10.4

9 Indonesia 7 9 Russian federation 10.3

10 Mexico 6.8 10 Egypt 8.6

2Version 1.3

Number of people with diabetes (20-79 years), 2010 and 2030Adapted from: The International Diabetes Federation, Diabetes Atlas Fourth Edition (2009). Available at: http://www.eatlas.idf.org/. Accessed: March 09, 2010

Recent NEJM Publication, March 2010China has the highest number of Adult diabetics: 92.4 million

Overview Which glycemic prameters to control?

Challenges of Hypoglycemia, Weight gain & Patient adherence to therapy?

Which hormonal abnormalities to control?

Evidence for Saxagliptin in comprehensive glycemic control in Type 2 DM

Riddle MC. Diabetes Care. 1990;13:676-86.

HbA1c reflects both fasting and postprandial hyperglycaemia

300

200

100

(mmol/L) (mg/dL)

Postprandialhyperglycaemia

Normal

Fasting hyperglycaemia

Time of day

0600 1200 1800 2400 0600

15.0

10.0

5.0

0

Plasma glucose

0

HbA1c

=Fasting Glucose

Postprandial Glucose

+

FPG influenced by:› Hepatic glucose production› Hepatic sensitivity to insulin› Exercise during the previous day› Meal from the previous night› Alcohol› Obstructive sleep apnoea› Nocturnal hypoglycaemia

PPG influenced by:› Pre-prandial glucose› Glucose load from meal › Incretin level› Insulin secretion› Insulin sensitivity in peripheral tissues › Decrease in glucagon suppression

Achieving HbA1c target requires an action on both FPG and PPG

IDF. International Diabetes Foundation. Diabetes Atlas. Third Edition. http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf. Accessed 26 Jan, 2009.

DECODE Study: Relative Risk of Mortality Increased with Increasing 2-Hr Glucose Level

Haz

ard

rat

io

Fasting Plasma Glucose (mM)

2-h

Pla

sma

Glu

cose

(mM

)

0

1

2

<6.1 6.1-6.9 >7.0

<7.87.8-11.0

>11.1

DECODE Study Group. Lancet 1999;354:617-621.

7Version 1.3

Appropriate A1C Management Should Consider Both

FPG and PPG Levels

FPG and PPG contributions to A1C differ as A1C levels change PPG is the major contributor

to A1C in patients with A1C <7.3%

FPG is the major contributor to A1C in patients with A1C ≥9.3%

Approximate Contribution to A1C (%)

>10.2

9.3–10.2

8.5–9.2

7.3–8.4

<7.3

A1C (%)FPGPPG

70%*† 30%†

53%‡ 47%‡

45% 55%

40%* 60%

30%* 70%

*Significant difference was observed between FPG and PPG.†Significantly different from all other quintiles.‡Significantly different from >10.2 quintile.All percentages are approximated.Monnier L et al. Diabetes Care. 2003;26:881-885.

FPG and PPG concentrations were measured in 290 patients with T2DM. Patients were divided into quintiles of A1C and these values were used to calculate the relative contribution that each made to the patient’s overall diurnal hyperglycemia. The results were compared across quintiles.

Different measures provide varying insightsHbA1c as an indicator of glycaemic control

Haemoglobin A1c (HbA1c) is an effective measure to evaluate the overall control of diabetes and risk of complications

HbA1c levels can be directly correlated to glucose levels1 and complications2

HbA1c is the preferred measure according to international guidelines (e.g. ESC/EASD)3

FPG and PPG as measures of glycaemic control Measuring FPG and PPG allows daily variations in

glucose levels to be assessed, compared with HbA1c4

PPG should be measured 2 hours after a meal as part of SMBG monitoring4

PPG correlates with CV risk5,6

Acute glucose variations detected postprandially may be an important indicator of oxidative stress7,8

1. Nathan DN, et al. Diabetologia. 2007;50:2239-44. 2. DCCT Study. Diabetes. 1995;44:968-83. 3. Rydén L, et al. Eur Heart J. 2007;28:88-136. 4. International Diabetes Foundation. Available at: http://www.idf.org. Accessed: 29 Jun, 2009. 5. DECODE Study Group. Lancet. 1999;354:617-21. 6. Hanefeld M, et al. Diabetologia. 1996;39:1577-83. 7. Monnier L, et al. JAMA. 2006;295:1681-7. 8. Brownlee M. Diabetes. 2005;54:1615-25.

.

Hence, Comprehensive Glycemic Control is Important in all Type

2 DM

AACE 2010 Along with HbA1c,

Consideration of both fasting and post-prandial glucose levels as end points

Risk for Retinopathy in Conventional and Intensive Treatment Subgroups of

the DCCT

The DCCT Study Group: Diabetes 44:968-83, 1995

Conventional

Intensive

Postprandial hyperglycemia and the risk for diabetic complications

....mean HbA1c is not the most complete expression of the degree of hyperglycaemia. Other features of diabetic control, which are not

reflected by HbA1c may add to or modify the risk for complications. For example, the risk for complications may be more highly

dependent on the extent of postprandial glycaemic excursions....

DCCT Study Group, Diabetes 1995

Hence, Postprandial glycemic excursions Control is Important

in all Type 2 DM

Kahn SE et al. N Engl J Med. 2006;355:2427-2443.

40

30

20

10

0

Glyburide

Metformin

Rosiglitazone

0 1 2 3 4 5

Years

Cumulative

incidence of mono-therapy failure*

(%)

Hazard ratio (95% CI) Rosiglitazone vs metformin, 0.68 (0.55–0.85), P<0.001 Rosiglitazone vs glyburide, 0.37 (0.30–0.45), P<0.001

N=4351

*Time to FPG >180 mg/dL

Hence, Sustained comprehensive glycemic Control is Important in

all Type 2 DM

Hazard Ratio

(HR lower CL,

HR upper CL)

Hypoglycaemia – a major predictor of cardiovascular death in the VADT

study

Prior event

HbA1c

HDL

Age

3.116 (1.744, 5567)

1.213 (1.038,1.417)0.699 (0.536, 0.910)2.090 (1.518, 2877)

120 2 4 6 8 10

P Value

Hypoglycaemia 4.042 (1.449,11.276)

Duckworth W.(VADT): results. 2008. Available from http://webcasts.prous.com/netadmin/webcast_viewer/Preview.aspx?

type=0&lid=3853, Accessed: 20 Oct 2009.

<0.01

0.02

0.01

<0.01

0.01

Recent hypoglycaemia is associated with

a higher risk of MI in diabetes patients

• Risk of MI associated with episodes of hypoglycaemia within a given prior period

Miller DR, et al. Poster Presentation at 45th EASD. Sep 29 – 2 Oct 2009, Vienna, Austria.

Any hypoglycaemiain specific periods

Index date or day before

Prior 2 weeks

Previous 5.5 months

Previous 6 months

Previous year

Casesof MI(%)

2.9

1.1

6.0

4.8

9.6

Controls(%)

0.1

0.3

2.5

2.1

4.2

Adjusted risk of MI(95% CI)

—

1.65 (1.50–1.81)

1.20 (1.15–1.25)

1.11 (1.06–1.15)

1.12 (1.08–1.16)

Hypoglycaemia and CV events

• In the ACCORD study and VADT, a clear association between severe hypoglycaemia and CV events was found1,2

(although no cause-effect relationship was proven)•

• Hypoglycaemia may be of particular concern in:• Obese patients• Individuals with a long duration of type 2 diabetes –

such as elderly patients, especially those with previous CV events3,4

1. Byington RP for the ACCORD Study Group. Accessed: 9 Oct 2009. 2. Duckworth W, et al. N Engl J Med. 2009;360:129-39. 3. Del Prato S. Diabetologia. 2009;52:1219-26. 4. Mannucci E, et al. Nutr Metab Cardiovasc

Dis. 2009;19:604-612.

Hence, avoidance of hypoglycemia is very important consideration

Obesity and insulin resistanceFFAs thought to:

stimulate glucose production by the liver

interfere with its ability to remove and respond to insulin

high levels of FFAs toxic to pancreatic β-cells (lipotoxicity)

TNF-α thought to: influence insulin resistance by

promotion of lipolysis, leading to increased FFA levels

Influence of FFAs on the liver

LipotoxicityLong-term exposure to high levels of FFAs increases destruction of

β-cellsEffect enhanced by hyperglycaemia

n=at baseline1

Conventional treatment (n=411); diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/L

UKPDS: up to 8 Kg in 12 years1

ADOPT: up to 4.8 Kg in 5 years2

Treatment difference (95% CI)Rosiglitazone vs metformin 6.9 (6.3 to 7.4); P<0.001Rosiglitazone vs glibenclamide, 2.5 (2.0 to 3.1); P<0.001

Annualised slope (95% CI) Rosiglitazone, 0.7 (0.6 to 0.8) Metformin, -0.3 (-0.4 to -0.2)** Glibenclamide, -0.2 (-0.3 to 0.0)**

Most current therapies result in weight gain over time

1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65. 2. Kahn SE, et al (ADOPT). N Engl J Med. 2006;355:2427-43.

Weig

ht

(Kg

)

Years

96

92

88

0

100

Glibenclamide (n=277)

Years from randomisation

Insulin (n=409)

Metformin (n=342)

Ch

an

ge in

weig

ht

(Kg

)

0

1

5

0 3 6 9 12

8

7

6

4

3

2

0 1 2 3 4 5

Hence, avoidance of Weight gain is very important consideration

Frequency of daily doses affects concordance

20

40

60

80

Op

tim

al con

cord

an

ce (

%)

**

Three-times-daily

*

Twice-dailyOnce-daily

*P<0.05; **P<0.01 vs once-daily administration

Guillausseau PJ. Treat Endocrinol. 2005;4:167-75.

Percentage of people with type 2 diabetes with optimal self-reported concordance with oral glucose-lowering agents

(no omission) according to the frequency of daily doses

Hence, therapies with once daily dosing improve ease of administration, patient adherence and overall glycemic control

Emergence of Diabetes as a Multihormonal Disorder: A Historical Perspective

Exen

atid

e

Sita

glip

tin

b cells

1925 200019751950

a cells

Disco

very

Insu

lin a

nalo

gues

Pum

p th

erap

y

Hum

an in

sulin

Zinc

insu

lin

NPH

insu

lin

InsulinAmylin

Disco

very

Amyl

in a

nalo

gue

Pram

lintide

Glu

cago

n

anta

goni

sts

Disco

very

Glucagon

GLP-1Ex

endi

n-4

and

G

LP-1

ana

logu

es

L cellsDisco

very

Adapted from Hirsch IB. NEJM. 2005;352:174-183; Drucker DJ. Cell Metab. 2006; 3:153-165; Singh-Franco D et al. Clin Ther. 2007;29:535-562.

SAXAGLI

PTIN

Hence, all hormonal abnormalities needed to be targeted to achieve

glycemic control

Wish List

A drug that can be used forSustained comprehensive glycemic control with

lower postprandial glycemic excursionsSafer: Low hypoglycemic risk & Weight neutralImproves patient adherenceTargets all hormonal abnormalities of diabetes

pathophysiology

AACE 2010 Goals as priorities in the selection of

medicationsInclusion of major classes of FDA-approved glycemic

medication, including incretin-based therapies Minimizing risk and severity of hypoglycemia Minimizing risk and magnitude of weight gain Consideration of both fasting and postprandial

glucose levels as end points In many cases, delaying pharmacotherapy to allow for lifestyle

modifications is inappropriate because these interventions are usually not adequate

Consideration of total cost of therapy to the individual and society at large, including costs related to medications, glucose monitoring requirements, hypoglycemic events, drug-related adverse events, and treatment of diabetes-associated complications

The major cost is related to the treatment of the complications of diabetes. We believe that identification of the safest and most efficacious agents is essential.

Hence, our Wish list matches with AACE 2010 criteria for selection of medications

22Version 1.3

α

βIncretin Effect

Decreased Glucose Production

Increased Glucose

UptakeMuscle

Liver

Glucose Homeostasis

Pancreatic cells respond to high levels of incretins

2

In response to meals, incretin hormones (GIP and GLP-1) are increasingly released from the small intestine

Glucagon Secretion

Insulin Secretion

Fat

Incretins (GIP/GLP-1)

Pancreatic alpha cell

Pancreatic beta cellβ

α

1

GI TractPancreas

DPP-4 enzymes break down incretins

3

DPP-4Enzymes

Indirect suppression of glucagon

GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1; DPP-4=dipeptidyl peptidase-4. 1. Kim W et al. Pharmacol Rev. 2008;60:470-512.2. Drucker DJ. Cell Metab. 2006;3:153-165.

23Version 1.3

Pancreasα

βDiminished

Incretin Effect

Increased Glucose

Production

Impaired Glucose

UptakeMuscle

Liver

Hyperglycemia

Fat

Insulin Secretion

Glucagon Secretion

β

α



Pancreatic beta cell

GI Tract

DPP-4Enzymes

In adults with T2DM, incretins are released, but the incretin-mediated effects are diminished

1

Incretin action on pancreatic cells is reduced

2

Less indirect suppression of glucagon

1. Kim W et al. Pharmacol Rev. 2008;60:470-512.2. Drucker DJ. Cell Metab. 2006;3:153-165.

24Version 1.3

DecreasedGlucose

Production

Increased Glucose

UptakeMuscle

Liver

Insulin Secretion

Fat

Glucose HomeostasisPancreasIncretin Effect

Muscle

Liver

Fat

GI Tract

DPP-4Enzymes

Saxagliptin, a DPP-4 inhibitor, sustains the effects of incretins in adults with T2DM

1



Pancreatic beta cellβ

α

Saxagliptin

Saxagliptin, a DPP-4 Inhibitor, Enhances the Body’s Natural

Response to Food1,2

Pancreatic cells respond to higher levels of incretins

2O

O

Glucagon Secretion

α

β Indirect suppression of glucagon

1. Kim W et al. Pharmacol Rev. 2008;60:470-512.2. Drucker DJ. Cell Metab. 2006;3:153-165.

Saxagliptin lowers FPG and PPG in a glucose dependant manner

A Review of the EvidenceA Proven Partner to Improve Glycemic

Control

25Version 1.3

Indication and Important Limitations of Use

GLP1 is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

Please see full Indian Prescribing Information available at this presentation.

Chemical Structure of DPP4 Inhibitors

• Vildagliptin’s nitrile group interacts with ser630 in the DPP4 active site

• Sitagliptin and alogliptin interact with glu205/glu206 in the DPP4 active site

• Saxagliptin’s compact structure fits more tightly into the DPP4 active site- Provides extended binding at 37°C- Strong interactions with ser630, tyr547, and glu205/glu206 in

the DPP4 active site - Most potent DPP4 inhibitorBYETTA/ LIRAGLUTIDE

SaxagliptinKi = 1.3 nM

VildagliptinVildagliptinKi = 13 nMKi = 13 nM

SitagliptinSitagliptinKi = 18 nMKi = 18 nM AlogliptinAlogliptin

Ki = 13 nMKi = 13 nM

GLP1/DPP IV Along With Diet and Exercise Provided Improved

Comprehensive Glycemic Control

27Version 1.3

GLP1/ DPP 1V Has Been Proven in Well-Controlled Clinical Trials

28Version 1.3

Add-On to a TZD (N=565)

Entry A1C: 7.0%–10.5%

Add-On to the SUGlibenclamide

(N=768) Entry A1C: 7.5%–10.0%

Add-On CombinationTherapy Trials

(N=2076)

Add-On to MET(N=743)

Entry A1C: 7.0%–10.0%

ANOLOGUE INSULINS

RAPID ACTING INSULINS HUMOLOG PLAIN/ HUMALOG MIX 25/75 HUMALOG

MIX 50/50USEFUL IN CLINICAL SETTINGS LIKE IN-PATIENT/

PREGNANCY/ RENAL FAILURE/OUT-PATIENT CAREMORE PHYSIOLOGICALBETTER PPBG CONTROL, LESS HYPOGLYCAEMIA

CONCLUSION

FBS/PPBS/HBA1C ALL NEEDS TO BE CONTROLLEDHYPOGLYCEMIA/ WEIGHT GAIN EQUALLY DANGEROUSMULTI-HORMONAL APPROACHANOLOGUE INSULINS RESULTED IN MORE

PHYSIOLOGICAL REDUCTION IN BLOOD SUGARSINCRETIN BASED THERAPY IS VERY USEFUL

THANK YOU

32Version 1.3

Shanti

Current Chart• Occupation: Teacher• Diagnosed with T2DM 5 years ago• Current MET dose 1500 mg/day• Hypertensive• Sedentary lifestyle• Non proliferative retinopathy

Latest Blood Glucose Values

•A1C: 8

•FPG: 150 mg/dl

•PPG: 210 mg/dl

45yAge: 150 cmHeight:IndianRace/Ethnicity: 65 kgWeight:

Discussion questions• What action would you take?

Not actual patient

Abd circum :90 cm

33Version 1.3

Saxagliptin as Add-On Combination Therapy With MET

Number of Patients743 adult patients with T2DM and inadequate glycemic control on MET alone

A1C Entry Criteria 7%–10%Duration 24 weeks

Base TherapyMET (1500 mg to 2550 mg daily) for at least 8 weeks

Lead-in Therapy

Single-blind, 2-week, diet and exercise placebo (PBO) lead-in period, during which patients received MET at their prestudy dose, up to 2500 mg daily, for the duration of the study

Treatment Arms* 4 arms: Saxa 2.5 mg + MET, Saxa 5 mg + MET, saxagliptin 10 mg + MET, PBO + MET

Rescue ProtocolPioglitazone added on to existing study medications

*Dose titrations of Saxagliptin and MET were not permitted.

In addition to diet and exercise

34Version 1.3

Change in A1C at 6 Months*Change in A1C at 6 Months* Percentage of Patients Achieving Percentage of Patients Achieving A1C <7% at 6 MonthsA1C <7% at 6 Months

Percentage of Patients Achieving Percentage of Patients Achieving A1C <7% at 6 MonthsA1C <7% at 6 Months

P<0.0001 vs placebo + MET-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(%

)

–0.7%

+0.1%

Saxagliptin 5 mg + MET (n=186)

Mean baseline: 8.1 %

Placebo + MET (n=175)


Pe

rce

nta

ge

of

Pa

tie

nts

(%

)

0.0

20.0

40.0

60.0





44%

17%

P<0.05 vs placebo + MET

80.0

100.0

*Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy.


35Version 1.3 M

ean

Ch

ang

e F

rom

Bas

elin

e* (

%)

Weeks

-1.0

-0.4

0.0

0.4

BL 4 6 8 12 16 20 24LOCF

24

-0.8

-0.6

-0.2

0.2

*Includes patients with a baseline and week 24 value. Week 24 (LOCF) includes intent-to-treat population using last observation on study prior to pioglitazone rescue therapy for patients needing rescue. Mean change from baseline is adjusted for baseline value.


Placebo + MET

Saxa 5 mg + MET

36Version 1.3

Change in 2-Hour PPG† at 6 Months*

Change in 2-Hour PPG† at 6 Months*Change in FPG at 6 Months*Change in FPG at 6 Months*


Mean baseline: 175 mg/dL

-60

-50

-40

-30

-20

-10

0

10

+1 mg/dL

–22 mg/dL

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)


–23 mg/dLGreater Reduction When Saxagliptin 5 mg Added



-70





-60

-50

-40

-30

-20

-10

0

10

–58 mg/dL

–18 mg/dL


Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)

-70

*Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. †As part of a 3-hour oral glucose tolerance test (OGTT).


37Version 1.3

HbAHbA1c1c Mean Change From Baseline Mean Change From Baseline (LOCF) at Week 102 (LOCF) at Week 102

Baseline HbA1c: 8.0 - 8.1%

Diabetes duration: 6.3 - 6.7 years

0.0

-0.4

-0.2

0.4

0.2

-0.6Hb

A1c

(%

) M

ea

n Δ

Fro

m B

L±S

E

BL 4 8 2012 30 37 50 63 76 89 102Weeks

PBO + METSAXA 5mg + MET

Ravichandran S, et al. Diabetologia 2009; 52(Suppl. 1):S60 [Abstract] & Oral Presentation at EASD 2009

Saxagliptin when used for early addition provides sustained comprehensive

glycemic control

38Version 1.3

-9.0

9.0

0.0

12.0

Ad

just

ed M

ean

Ch

ang

e in

F

PG

(m

g/d

L)

± S

E

FPG

6.0

3.0

-3.0

-6.0

-12.0

-15.0 -11

Dosen observed=

BL mean

5+MET31

179

PBO+MET15

175

SAXA (mg)

PBO + METSAXA 5mg + MET

-40

0.0

10A

dju

sted

Mea

n C

han

ge

in 1

20-m

in

PP

G (

mg

/dL

) ±

SE

-4

120-min PPG

3.0

-20

-30

-50

-35

Dosen observed=

5+MET46

PBO+MET24

SAXA (mg)

10

50

Per

cen

tag

e o

f p

atie

nts

Ach

ievi

ng

H

bA

1c <

7% (

95%

CI)

12

HbA1c <7%

40

30

20

0

30

Dosen observed=

5+MET13

PBO+MET15

SAXA (mg)

SAXA: Saxagliptin; MET: Metformin; PBO: Placebo

Ravichandran S, et al. Diabetologia 2009; 52(Suppl. 1):S60 [Abstract] & Oral Presentation at EASD 2009

HbAHbA1c1c Mean Change From Baseline Mean Change From Baseline (LOCF) at Week 102 (LOCF) at Week 102

Saxagliptin plus metformin leads to more balanced glycaemic control

Combination of Saxa plus metformin leads to more balanced glucose control

Saxa plus metformin as

first-line therapy for treatment-naïve patients with uncontrolled type 2 diabetes may lead to fewer glucose excursions, that result in hypo- or hyperglycaemia

Glucose excursion profiles at baseline and week 24

Saxagliptin reduces postprandial glycemic excursions

Saxagliptin 5 mg Together With MET Gave Medication-Naive Adult Patients Greater Glycemic Control vs MET Plus Placebo

40Version 1.3

Saxagliptin as Initial Combination With MET

Number of Patients1306 treatment-naive adult patients with T2DM with inadequate glycemic control on diet and exercise alone

A1C Entry Criteria 8% to 12%

Duration 24 weeks

Base Therapy N/A (patients were treatment-naive)

Lead-in TherapySingle-blind, 1-week, dietary and exercise placebo lead-in period

Treatment Arms*

4 arms: Saxagliptin 5 mg + MET, saxagliptin 10 mg + MET, saxagliptin 10 mg + PBO, MET + PBO

Rescue Protocol Pioglitazone rescue as add-on therapy

*The MET dose was up-titrated weekly in 500 mg/day increments, as tolerated, to a maximum of 2000 mg/day based on FPG.


Saxagliptin Together With MET Gave Medication-Naive Adult Patients Greater

Glycemic Control

41Version 1.3

Change in A1C at 6 Months*Change in A1C at 6 Months*

MET + Placebo (n=313)

Mean baseline: 9.4%

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(%

)

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0

–2.0%


Mean baseline: 9.4%

–2.5%

P<0.0001 vs MET + placebo

P<0.05 vs MET + placebo

Percentage of Patients Achieving A1C <7% at 6 Months


Pe

rce

nta

ge

of

Pa

tie

nts

(%

)0.0

20.0

40.0

60.0

Saxagliptin 5 mg + MET

(n=307)Mean baseline: 9.4%

MET + Placebo(n=314)

Mean baseline: 9.4%

41%

80.0

100.0

60%

*Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. Metformin was initiated at a starting dose of 500 mg daily, up-titrated to 1000 mg at Week 1, and thereafter up-titrated as tolerated to a maximum of 2000 mg daily based on FPG through Week 5.


Saxagliptin With MET as Initial Combination Delivered Statistically Significant Reductions

in FPG and PPG

42Version 1.3

Change in FPG at 6 Months*Change in FPG at 6 Months* Change in 2-Hour PPG† at 6 Months*


MET + Placebo (n=320)




MET + Placebo(n=141)




-120

-100

-80

-60

-40

-20

0

20

–60 mg/dL

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)

-120

-100

-80

-60

-40

-20

0

20

–138 mg/dL

–97 mg/dL

-140P<0.05 vs MET + placebo

-140P<0.05 vs MET + placebo

–47 mg/dL

*Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. †As part of a 3-hour OGTT.


43Version 1.3

Leela

Current Chart

• Occupation: School teacher

• Diagnosed with T2DM 5 years ago

• Lean

• Currently on 7.5 mg glibenclamide daily

• Sedentary lifestyle

• Non proliferative retinopathy

Latest Blood Glucose Values

• A1C: 8.1

• FPG: 148 mg/dl

• PPG: 228 mg/dl

45yAge: 150 cmHeight:IndianRace/Ethnicity: 52 kgWeight:

Not actual patient

Abd circum :70 cm

Discussion questions• What would you do now? Up-titrate GlIB? Add a second agent?

• What other factors would you consider in her treatment?

44Version 1.3

Saxagliptin as Add-On Combination Therapy With GLY

Number of Patients768 adult patients with T2DM with inadequate glycemic control on a submaximal dose of the SU glibenclamide alone

A1C Entry Criteria 7.5%–10%

Duration 24 weeks

Base Therapy Submaximal dose of Glib for 2 months or greater

Lead-in TherapySingle-blind, 4-week, diet and exercise lead-in period, and placed on GlIB 7.5 mg once daily

Treatment Arms* 4 arms: Saxagliptin (2.5 or 5 mg) + 7.5 mg GLIB, PBO + 10 mg GLIB

Rescue Protocol MET rescue, added on to existing study medication

*Patients who received placebo were eligible to have Glib up-titrated to a total daily dose of 15 mg. Up-titration of GLIB was not permitted in patients who

received Saxagliptin 2.5 mg or 5 mg. Dose titration of Saxagliptin was not permitted during the study.


Saxagliptin 5 mg Added to a Submaximal Dose of GLIB: A1C Results

45Version 1.3

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

P<0.0001 vs placebo + up-titrated GLY

Saxagliptin 5 mg + GLIB 7.5 mg (n=250)

Mean baseline: 8.5%

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(%

)

–0.6%


Percentage of Patients Achieving A1C <7% at 6 MonthsChange in A1C at 6 Months*Change in A1C at 6 Months*

Placebo + Up-Titrated GLIB (n=264)

Mean baseline: 8.4%

+0.1%

Pe

rce

nta

ge

of

Pa

tie

nts

(%

)

0.0

20.0

40.0

60.0

23%

9%


Mean baseline: 8.5%


Mean baseline: 8.4%

80.0

100.0P<0.05 vs placebo + up-titrated GLIB

92% of patients in the placebo + SU group required up-

titration to the maximum SU study dose of 15 mg

*Intent-to-treat population using last observation on study prior to MET rescue therapy.


46Version 1.3







+8 mg/dL

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)

-40

-30

-20

-10

0

10

P<0.05 vs placebo + up-titrated GLIB





+1 mg/dL

–10 mg/dL

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(m

g/d

L)

-40

-30

-20

-10

0

10

–10 mg/dLImprovement When Onglyza 5 mg Added

P<0.05 vs placebo + up-titrated GLIB

-50

-60

-70

-50

-60

-70

–34 mg/dL

*Intent-to-treat population using last observation on study prior to MET rescue therapy. †As part of a 3-hour OGTT.


47Version 1.3

Saxagliptin as Add-On Combination Therapy With a TZD

Number of Patients565 adult patients with T2DM with inadequate glycemic control on TZD alone

A1C Entry Criteria 7%–10.5%

Duration 24 weeks

Base TherapyPioglitazone (30-45 mg once daily) or rosiglitazone (4 mg once daily or 8 mg either once daily or in two divided doses of 4 mg) for at least 12 weeks

Lead-In TherapySingle-blind, 2-week, diet and exercise placebo lead-in period, during which patients received TZD at their pre-study dose for the duration of the study

Treatment Arms* 3 arms: Saxagliptin (2.5 or 5 mg) + TZD, PBO + TZD

Rescue Protocol MET added on to existing study medications

*Dose titration of Onglyza or TZD was not permitted during the study.


48Version 1.3

Placebo + TZD(n=127)


Saxagliptin 5 mg + TZD (n=134)


Me

an

Ch

an

ge

Fro

m

Ba

se

lin

e (

mg

/dL

)-60

-50

-40

-30

-20

-10

0

10

–65 mg/dL

–15 mg/dL

-70P<0.05 vs placebo + TZD



Placebo + TZD(n=181)




-60

-50

-40

-30

-20

-10

0

10

–17 mg/dL

Me

an

Ch

an

ge

Fro

m

Ba

se

lin

e (

mg

/dL

)

–15 mg/dLGreater Reduction When

Onglyza 5 mg Added

–3 mg/dL

P<0.05 vs placebo + TZD -70

*Intent-to-treat population using last observation on study prior to MET rescue therapy. †As part of a 3-hour OGTT.


49Version 1.3

Change in A1C at 6 Months*Change in A1C at 6 Months*

*Intent-to-treat population using last observation on study prior to MET rescue therapy.

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

P<0.0001 vs placebo + TZD

Placebo + TZD (n=180)

Mean baseline: 8.2%

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(%

)


Mean baseline: 8.4%

–0.3%



P<0.05 vs placebo + TZD

Pe

rce

nta

ge

of

Pa

tie

nts

(%

)0.0

20.0

40.0

60.042%

26%

Placebo + TZD (n=180)

Mean baseline: 8.2%


Mean baseline: 8.4%

80.0

100.0

–0.9%


Summary of Efficacy

• Saxagliptin 5 mg provides consistent, clinically meaningful and statistically significant reductions in

• HbA1c

• FPG• PPG

• Saxagliptin 5 mg provides significant blood glucose lowering efficacy in addition to metformin or Sulphonylureas or Thiazolidinediones over 24 weeks

• The addition of saxagliptin 5 mg to metformin provided sustained clinically meaningful glycaemic improvements over 102 weeks

• Saxagliptin 5 mg also provides significant blood glucose lowering efficacy in monotherapy and in initial combination with metformin over 24 weeksSource: Approved India PI

Review of Safety and Tolerability

51Version 1.3

Please see full Indian Prescribing Information available at this presentation.

Saxagliptin: Incidence of Adverse Events

Overall Incidence of Adverse Events Was Similar to Placebo

Adverse reactions reported in ≥2% of patients treated with Saxagliptin 5 mg or Saxagliptin 2.5 mg and ≥1% more frequently compared to placebo, respectively, included:

Sinusitis: 2.6% and 2.9% vs 1.6%, respectively

Abdominal pain: 1.7% and 2.4% vs 0.5% Gastroenteritis: 2.3% and 1.9% vs 0.9% Vomiting: 2.3% and 2.2% vs 1.3%

Hypersensitivity-related events (such as urticaria and facial edema) were reported in 1.5%, 1.5%, and 0.4% of patients who received Saxagliptin 5 mg, Saxagliptin 2.5 mg, and placebo, respectively

52Version 1.3

Pooled Analysis of Adverse Reactions Occurring in ≥5% of Patients and More

Commonly Than Placebo

Pooled Analysis of Adverse Reactions Occurring in ≥5% of Patients and More

Commonly Than Placebo

Saxagliptin 5 mg

(N=882)

Placebo(N=799)

Upper respiratory tract infection

7.7% 7.6%

Urinary tract infection

6.8% 6.1%

Headache 6.5% 5.9%

In Monotherapy and Add-On Therapy Studies*

Percent of Patients

*Prespecified pooled analysis of 2 monotherapy studies, the add-on to MET study, the add-on to the SU glibenclamide study, and the add-on to a TZD study; 24-week data regardless of glycemic rescue.

Incidence of Adverse Events in Initial Combination With MET

In the initial combination with MET, the overall incidence of adverse events was 55% for Saxagliptin 5 mg plus MET vs 59% for MET plus placebo

53Version 1.3

Adverse Reaction Occurring in ≥5% Patients and More Commonly Than

MET Plus Placebo

Adverse Reaction Occurring in ≥5% Patients and More Commonly Than

MET Plus Placebo

Saxagliptin 5 mg

+ MET(N=320)

MET + Placebo (N=328)

Headache 7.5% 5.2%

Nasopharyngitis

6.9% 4.0%

In Initial Combination With MET Study*

Percent of Patients

*Metformin was initiated at a starting dose of 500 mg daily and titrated up to a maximum of 2000 mg daily.

Jadzinsky M et al. Diabetes Obes Metab. 2009;11:611-622.

Saxagliptin: Discontinuation of Therapy Due

to Adverse Events Discontinuation of therapy due to adverse events occurred in 3.3% and 1.8% of patients receiving Saxagliptin and placebo,

respectively There was a dose-related mean decrease in absolute lymphocyte count observed with Saxagliptin

54Version 1.3

Most Common Adverse Events Associated With Discontinuation of Therapy*

Most Common Adverse Events Associated With Discontinuation of Therapy*

Saxagliptin

5 mg (N=882)

Saxagliptin2.5 mg(N=882)

Comparator (N=799)

Lymphopenia 0.5% 0.1% 0.0%

Rash 0.3% 0.2% 0.3%

Blood creatinine increase 0.0% 0.3% 0.0%

Blood creatine phosphokinase increase

0.2% 0.1% 0.0%

Percent of Patients

*Reported in at least 2 patients treated with Saxagliptin

55Version 1.3

Incidence of Reported Hypoglycemia Across Phase 3 Clinical Trials

Incidence of Reported Hypoglycemia Across Phase 3 Clinical Trials

Saxagliptin

5 mg

Saxagliptin

2.5 mg

Comparator

Add-On to MET 5.8% 7.8% 5.0%

Initial Combo With MET 3.4% — 4.0%

Add-On to the SU Glyburide

14.6% 13.3% 10.1%

Add-On to a TZD 2.7% 4.1% 3.8%

Pooled Monotherapy 5.6% 4.0% 4.1%

Percent of Patients

Saxagliptin Plus GLIB: Incidence of Hypoglycemia

56Version 1.3

Incidence (%) of HypoglycemiaIncidence (%) of Hypoglycemia

•Use with Medications Known to Cause Hypoglycemia: Insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with Saxagliptin

Saxagliptin 5 mg +

GLIB 7.5 mg

Saxagliptin 2.5 mg +

GLIB 7.5 mg

Placebo + Up-Titrated

GLIB

Reported

Hypoglycemia*14.6% 13.3% 10.1%

Confirmed

Hypoglycemia†0.8% 2.4% 0.7%

Add-on to the SU Glibenclamide study

*Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required. †Defined as symptoms of hypoglycemia accompanied by a fingerstick glucose value of 50 mg/dL.

Saxagliptin has minimal risk of hypoglycemia

kg

SAXA 2.5 mg SAXA 5 mg SAXA 10 mg PBO

Monotherapy

(-011) -1.22 -0.05 -0.13 -1.35

(-038) -0.3 -0.9 -1.3

Add-on Combination

+ MET (-014) -1.43 -0.87 -0.53 -0.92

+ SU (-040) 0.7 0.8 0.3

+ TZD (-013) 1.3 1.4 .9

SAXA 5 mg + MET

SAXA 10 mg+ MET SAXA 10 mg MET

Initial Combinationwith MET (-039)

-1.8 -1.4 -1.1 -1.6

Pivotal Phase 3 Studies – ST Period Excluding RT

DeFronzo RA. Diabetes Care. 2009;32:1649-55 Hollander P. J Clin Endocrinol Metab. 2009;94(12):4810-19

Jadzinsky M. Diabetes, Obesity and Metabolism.2009;11:611-22

Saxagliptin is weight neutral

58Version 1.3Add onto Metformin TrialMost Frequent AEs by Treatment (Week

102)AEa SAXA 2.5 mg

+ METSAXA 5 mg

+ METSAXA 10 mg

+ METPBO + MET

n=192 n=191 n=181 n=179Influenza 20 (10.4) 22 (11.5) 23 (12.7) 23 (12.8)

Nasopharyngitis 25 (13.0) 21 (11.0) 25 (13.8) 19 (10.6)

Bronchitis 12 (6.3) 18 (9.4) 9 (5.0) 11 (6.1)

URTI 23 (12.0) 17 (8.9) 19 (10.5) 14 (7.8)

Headache 26 (13.5) 17 (8.9) 22 (12.2) 20 (11.2)

UTI 19 (9.9) 15 (7.9) 17 (9.4) 12 (6.7)

Back pain 15 (7.8) 15 (7.9) 9 (5.0) 16 (8.9)

Diarrhea 27 (14.1) 14 (7.3) 17 (9.4) 23 (12.8)

aValues are expressed as n (%). Five most frequent AEs by dose highlighted.URTI = upper respiratory tract infection; UTI = urinary tract infection.

Warnings and Precautions

Use with Medications Known to Cause Hypoglycemia: Insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with Saxagliptin

Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Saxagliptin or any other antidiabetic drug

59Version 1.3

Drug Interactions and Use in Specific Populations

Drug InteractionsSaxagloptin should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).

60Version 1.3

Use in Specific PopulationsPregnant and Nursing Women: There are no adequate and well-controlled studies in pregnant women. Saxagliptin, like other antidiabetic medications, should be used during pregnancy only if clearly needed. It is not known whether saxagliptin is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when Saxagliptin is administered to a nursing woman.Pediatric Patients: Safety and effectiveness of Saxagliptin in pediatric patients have not been established.

Saxagliptin: Renal safety

Mild Impairment, creatinine clearance [CrCl] >50 mL/min: No dosage adjustment

Moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis (creatinine clearance [CrCl] ≤50 mL/min). Saxagliptin 2.5 mg is recommended.

Saxagliptin should be administered following hemodialysis. Saxagliptin has not been studied in patients undergoing peritoneal dialysis.

Assessment of renal function is recommended prior to initiation of Saxagliptin and periodically thereafter.

61Version 1.3

Saxagliptin: Hepatic safety

In subjects with hepatic impairment (Child-Pugh classes A, B, and C) Mean Cmax and AUC of saxagliptin were up to 8% and 77%

higher, respectively, compared to healthy matched controls following administration of a single 10 mg dose of saxagliptin.

The corresponding Cmax and AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls.

These differences are not considered to be clinically meaningful. No dosage adjustment is recommended for patients with

hepatic impairment

62Version 1.3

63Version 1.3

Number (%) of subjects

SAXA2.5 mgn = 937

SAXA5 mg

n = 1,269

SAXA10 mg

n = 1,000All SAXA3

n = 3,356Control

n = 1,251

Subjects with at least one CV risk factor in addition to T2D

777 (83) 1,015 (80) 803 (80) 2,724 (81) 1,035 (83)

Hypertension 519 (55) 655 (52) 510 (51) 1,750 (52) 688 (55)

Hypercholesterolaemia1 471 (50) 565 (45) 353 (35) 1,475 (44) 566 (45)

Smoking history 383 (41) 449 (35) 393 (39) 1,301 (39) 471 (38)

First degree family member with premature coronary heart disease

190 (20) 248 (20) 186 (19) 677 (20) 265 (21)

Patients with prior CV disease2 118 (13) 150 (12) 118 (12) 404 (12) 165 (13)

1. Includes mixed dyslipidaemia2. Prior CV disease defined as previous myocardial infarction, congestive heart failure, hospitalisation for unstable angina, stable angina, percutaneous coronary intervention, coronary artery bypass graft, coronary artery disease, cerebrovascular disease, peripheral vascular disease3. Includes contribution from 20–100 mg saxagliptin in Phase 2b study. Data on file. AstraZeneca/Bristol-Myers

Squibb Alliance.

SAXA: Saxagliptin; CV: Cardiovascular.

Cardiovascular risk factors (in addition to T2D)Saxagliptin controlled Phase 2b/3 pooled population

64Version 1.3

Patients at riskControl 1,251 935 860 774 545 288 144 123 102 57All saxagliptin 3,356 2,615 2,419 2,209 1,638 994 498 436 373 197

Cardiovascular events: Saxagliptin controlled Phase 2b/3 pooled

population

Data on file. AstraZeneca/Bristol-Myers Squibb Alliance.

Time to onset of first primary Major Adverse Cardiovascular Event (MACE)*

All saxagliptin

Control

0 24 37 50 63 76 89 102 115 1280

1

2

3

4

5

Weeks

Fir

st a

dve

rse

even

t (%

)

* Primary MACE was defined as was defined as stroke (cerebrovascular accidents), MI, and CV death

Summary of Efficacy and Safety

Saxagliptin Provides meaningful benefits across key glycemic

parameters (HbA1c, PPG and FPG)

Provides a favourable safety and tolerability profile (low risk of hypoglycaemia, no or minimal differences in weight change compared with control, etc)

Provides reassurance of CV safety – no CV safety signal has been identified

Offers a treatment option with a favourable benefit/risk profile for people with type 2 diabetes not at glycaemic goal.

Source: Approved India PI

Convenient Once-Daily Dosing

Taken any time of day, with or without food

24-hour glycemic control

Single, one-step dose adjustment in

moderate-to-severe renal impairment or

ESRD requiring hemodialysis on Saxagliptin

5 mg

Dose of Saxagliptin should be limited to 2.5

mg when co-administered with a strong

CYP3A4/5 inhibitor*

No dosage adjustment based on gender,

race, weight, or hepatic impairment

66Version 1.3

Dosing Considerations for SaxagliptinDosing Considerations for Saxagliptin

Recommended Dose

orRecommended dose once daily taken regardless of meals

Moderate-to-severe renal impairment, or ESRD requiring hemodialysis (CrCl ≤50 mL/min)

Co-administration with strong CYP3A4/5 inhibitors*

Tablets Not Actual Size.

5 mg once daily 2.5 mg once daily

2.5 mg once daily

Saxagliptin has not been studied in patients undergoing peritoneal dialysis. Assessment of renal function is recommended prior to initiation of Saxagliptin and periodically thereafter

*Such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin.


ESRD= end-stage renal disease

Saxagliptin

can be used forEarly InterventionEarly additionSustained comprehensive glycemic control with lower

postprandial glycemic excursionsSafer: Low hypoglycemic risk & Weight neutralTargets all hormonal abnormalities of diabetes pathophysiology

Saxagliptin: A Proven Partner for the Ongoing Struggle With T2DM

Improved glycemic control by significantly reducing A1C and its key contributors—FPG & PPG

Provided significant A1C reductions when partnered with key OAD agentsMetformin, Glibenclamide, or a TZD

Overall incidence of adverse events similar to placebo

Weight and lipid neutral

Convenient, once-daily dosing

68Version 1.3

THANKS

70Version 1.3

Please see full US Prescribing Information available at this presentation

DPP-8/9 Inhibition and AEs: No Definitive Conclusions can be Drawn

A preclinical study in rats and dogs has led to controversy concerning the possibility of nonselective inhibition of DPP-8/9 enzymes increasing the potential for AEs1

Subsequent preclinical studies offered contradictory evidence, thus there is no conclusive evidence of a relationship between DPP-8/9 inhibition and AEs in animals2,3

DPP-8/9 are widely expressed enzymes. Research in animal cell models indicate localization in the digestive and immune systems4

Given contradictory animal data, limitation of extrapolating animal data to humans, and the limited clinical data, no definitive conclusions can be drawn about a link between AEs and DPP-8/9 inhibition in humans5

Pharmacology

AE=adverse event; DPP=dipeptidyl peptidase.1. Lankas GR et al. Diabetes. 2005;54:2988-2994. 2. Burkey BF et al. Diabetes Obes Metab. 2008;10:1057-1061. 3. Rosenblum JS et al. Poster presented at: American Diabetes Association; June 22-26, 2007; Chicago, IL.4. Yu DMT et al. J Histochem Cytochem. 2009. doi:10.1369/jhc.2009.953760.5. Barnett A. Int J Clin Pract. 2006;60(11):1454-1470.

What Effect Does Saxagliptin Have on Lymphocyte Counts and Infection Rates?

Weeks

Change from Baseline in Absolute Lymphocyte Counts (%)

* From Weeks 76 to 128, the two placebo-controlled trials included Fixed-Dose Monotherapy and Add-On to Metformin.Data combine short-term data (Week 24) and the most recently assessed long-term data (Week 128). Bristol-Myers Squibb Company. NDA 22-350. Available

at:http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM148109.pdf. Published March 2, 2009. Accessed March 10, 2010.

•Mean baseline absolute lymphocyte count: ~2200 cells/µL

Lym

ph

ocy

te P

erce

nt

Ch

ang

es

Fro

m B

ase

lin

e (%

)

-10128

-5

0

5

10

115102897663503724BL 126

Saxagliptin 5 mgPlacebo

5 Placebo-Controlled Trials 2 Placebo-Controlled Trials*

• There was a dose-related mean decrease in absolute lymphocyte count observed with saxagliptin

Adverse Events: Lymphocyte and Infections

Decreases in lymphocyte count were not associated with clinically relevant adverse reactions1,2

Clinical significance of this decrease in lymphocyte count relative to placebo is not known1,2

No difference in pattern of infection-related AEs for saxagliptin-treated subjects with lymphocyte count decreases as compared with saxagliptin-treated subjects in the overall population2

The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (eg, human immunodeficiency virus) is unknown1

AE=adverse event. 1. Onglyza [package insert]. India.2. Bristol-Myers Squibb Company. NDA 22-350. Available at:

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM148109.pdf. Published March 2, 2009. Accessed Mar 10, 2010

Adverse Reactions

What Skin-Related Adverse Events Have Been Seen With Saxagliptin Treatment?

Nonclinical Toxicology Saxagliptin produced adverse skin changes in the extremities of

cynomolgus monkeys (scabs and/or ulceration of tail, digits, scrotum, and/or nose)

Skin lesions were reversible at >20 times the MRHD but in some cases were irreversible and necrotizing at higher exposures

Adverse skin changes were not observed at exposures similar to

(1 to 3 times) the MRHD of 5 mg Clinical correlates to skin lesions in monkeys have not been

observed in human clinical trials of saxagliptin

MRHD=maximum recommended human dose. Source: Approved India PI

Adverse Reactions

What is the Effect of Saxagliptin on the Incidence of Pancreatitis?

Of the six patients with pancreatitis in the saxagliptin treatment groups, five patients had at least one known risk factor for pancreatitis (alcohol use, cholelithiasis, prior history of hypertriglyceridemia, or prior history of pancreatitis). One patient, in the saxagliptin 5 mg + MET group, had no known risk factors for pancreatitis

* Includes subjects who were later uptitrated in the monotherapy dose-regimen study. † Includes the Open Label cohort in the monotherapy fixed-dose study. ‡ Includes data from higher dose groups in the Phase IIb dose-ranging study; therefore, numbers across the rows are not additive.§ Combined placebo groups from all Phase IIb/III studies, including the MET monotherapy group from the initial combination with MET study.║ Includes rescue therapy.

AE=adverse event; PT=preferred term; MET=metformin.Data combine short-term data (24 weeks) and the most recently assessed long-term data. Long-term phase for each study varies from 2 to 4 years.

1. Bristol-Myers Squibb Company-AstraZeneca. Saxagliptin BMS-477118. Part Two. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM149589.pdf. Published May 8 2009. Accessed November 05, 2009.

2. Bristol-Myers Squibb Company. NDA 22-350. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM148109.pdf. Published March 2, 2009. Accessed November 5, 2009.

Saxagliptin 2.5 mg*

n=937

Saxagliptin 5 mg*

n=1269

Saxagliptin 10 mg†

n=1066

All Saxagliptin‡

n=3422

Comparator§

n=1251

All AEs of Pancreatitis║ 1 (0.1%) 3 (0.2%) 2 (0.2%) 6 (0.2%) 2 (0.2%)

Pancreatitis PT 0 2 (0.2%) 1 (0.1%) 3 (0.1%) 1 (0.1%)

Acute Pancreatitis PT

0 1 (0.1%) 1 (0.1%) 2 (0.1%) 0

Chronic Pancreatitis PT

1 (0.1%) 0 0 1 (<0.1%) 1 (0.1%)

Adverse Reactions

422US09PSM41201 278438

Dermatological safety –overviewMulti-focal reversible skin lesions (erosions and ulcers) observed in

cynomolgus monkeys exposed to saxagliptin

Phase 3 safety monitoring included investigator training, supplemental data collection with special case-report forms

Analyses performed based on pre-defined Medical Dictionary for Regulatory Activities (MedDRA) preferred terms similar to non-clinical findings in monkeys

Terms included skin ulcer, erosion, and necrosis

Events infrequent – none led to study drug discontinuation

None considered to be related to study drug

Based on the clinical programme, no evidence was observed for human clinical data correlating to monkey skin findings

Saxagliptin, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Briefing Document for April 2009 Meeting: NDA 22-350. Available at: http://www.fda.gov/OHRMS/DOCKETS/ac/09/briefing/2009-4422b1-02-Bristol.pdf. Accessed: Mar 10, 2010.

Lymphocyte count analyses – overviewDose-dependent reductions in lymphocyte count were observed in Phase 1 and

2b studies at higher doses

In Phase 3 studies, a small dose-dependent reduction in mean absolute lymphocyte count was observed with the 5 and 10 mg doses

Decline with 5 mg dose approximately 100 c/µL relative to PBO from baseline mean lymphocyte count of approximately 2200 c/µL

Decreases were non-progressive with daily dosing of saxagliptin up to 128 weeks

Lymphocyte decreases not associated with clinical adverse consequences

In subjects with low lymphocyte counts, the types of infections observed were similar to those in the general population (i.e. no unusual opportunistic infections)

Comparable infection-related AE rates were observed for saxagliptin 5 mg and placebo without signal for opportunistic events in the overall population

Saxagliptin, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Briefing Document for April 2009 Meeting: NDA 22-350. Available at: http://www.fda.gov/OHRMS/DOCKETS/ac/09/briefing/2009-4422b1-02-Bristol.pdf. Accessed: Mar 10, 2010

Saxagliptin 5 mg as Recommended Usual Clinical Dose

Consistent efficacy benefit observed for saxagliptin 5 mg versus 2.5 mg as monotherapy, and add-on treatment (MET, TZD, SU)

Results consistent with observations of greater DPP4 inhibition at trough with 5 mg versus 2.5 mg dose

No evidence for incremental efficacy benefit for 10 mg versus 5 mg dose in key glycemic parameters

Given the comparable safety profile of the 2.5 and 5 mg doses, saxagliptin 5 mg is the proposed usual clinical dose


-0.51

-0.61

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

A

1C

(%

) w

ith

9

5%

CI

Difference from Placebo in Adjusted Mean Change from Baseline in A1C

Phase 2b/3 Monotherapy Phase 2b/3 Monotherapy Studies Post-hoc Pooled Studies Post-hoc Pooled Analysis (Wk 12)Analysis (Wk 12)

PooledPooledSAXA SAXA

2.5 mg2.5 mg

PoolePooledd

SAXA SAXA 5 mg5 mg

SAXA + SAXA + METMET(014)(014)

2.5 mg2.5 mg5 5 mgmg

-0.62

-0.36

-0.73 -0.72

-0.63

-0.83

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Phase 3 Add-on Combination Phase 3 Add-on Combination Studies ST Period (Wk 24)Studies ST Period (Wk 24)SAXA + SAXA +

TZDTZD(013)(013)

2.5 mg2.5 mg5 5 mgmg

SAXA + SAXA + SUSU

(040)(040)2.5 mg2.5 mg5 5

mgmg


1version 1.3 dr mohan k rao md fellowship in diabetes & endocrinology (utsw medical center,...

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