Pramlintide

– An analog of amylin that overcomes the tendency of human amylin to:

• Aggregate, form insoluble particles • Adhere to surfaces

– Pharmacokinetic and pharmacodynamic properties similar to human amylin

Human amylin Pramlintide (analog of amylin)

AmideS S

AY

T

N

SG

V NT

T TT

N

AA

A

LI

KS

SC

CQ

RL N

NNF

G

FL

VH

Amide

PP

P

YT

N

SG

V NT

T TT

N

AA

A

L

I

KS

SC

CQ

RL N

NNF

G

FL

VH

Adapted from Young A, et al. Drug Dev Res 1996; 37:231-248Adapted from Westermark P, et al. Proc Natl Acad Sci 1990; 87: 5036-5040

Pramlintide Mimicked Three Important Actions of Amylin That

Impact Glucose Appearance

Amylin* Pramlintide

Slows gastric emptying

Promotes satiety and reduces caloric intake

Inhibits inappropriately high postprandial glucagon secretion

*All amylin studies were performed in animalsPramlintide Acetate Injection US Prescribing Information, 2005

Pramlintide Reduces Postprandial Glucagon

T1DM

Time (h)

PlaceboPramlintide

Placebo or 25 µg/h pramlintide infusion-20

0

10

20

30

-10

InsulinSustacal

0 2 3 4 51

T2DM, Late Stage

Time (h)

Pla

sma G

luca

gon

(pg

/mL)

InsulinSustacal60

40

30

50

Placebo or 100 µg/h pramlintide infusion

0 1 2 3 4 5

P

lasm

a G

luca

gon

(p

g/m

L)

T2DM, n = 12; AUC1-4 h: P = 0.005T1DM, n = 9; AUC1-5 h: P<0.001; Data from: Fineman M, et al. Metabolism. 2002;51:636-641. Fineman M, et al. Horm Metab Res. 2002;34:504-508.

% Emptied per hrafter breakfast

Placebo 30 μgPramlintide

60 μgPramlintide

Pramlintide Slowed Gastric Emptying-

T1DMInsulin + Placebo

Insulin + Pramlintide

Type 1 diabetes; single SC pramlintide doses: n = 11, crossover 99m Tc labelled pancake; solid component measuredCalculated from Kong MF, et al. Diabetologia 1998; 41:577-583

Gastric Emptying Is Accelerated in

T1DM

Nowak TV, et al. Gastroenterology 1990; 98:A378;

Pramlintide Reduced Caloric Intakein Type 2 Diabetes

0

250

500

750

1000

1250

Protein

CHO

Fat

CHO

Fat

Protein

-202 kcal(-23%)P <0.01

Ad-LibitumCaloric Intake

(kcal)

PlaceboPramlintide

n = 11; subjects given buffet meal Pramlintide (single SC injection, 120 μg)Data from Chapman I, et al. Diabetologia 2005; 48:838-848

Pramlintide Improved Postprandial Glucose

100

150

200

250

300

0 60 120 180 240

Time Relative to Meal and Pramlintide (min)

Mean (SE) Plasma Glucose (mg/dL)

100

150

200

250

300

0 60 120 180 240

Mean (SE) Plasma Glucose(mg/dL)

Lispro InsulinPramlintide 60 μg + Lispro Insulin

Regular InsulinPramlintide 60 μg + Regular Insulin

TYPE 1 DIABETESTYPE 1 DIABETES

Evaluable; Mean (SE)Pramlintide + Lispro insulin, n = 20; Pramlintide + Regular insulin, n = 18Data from Weyer C, et al. Diabetes Care 2003; 26:3074-3079; Pramlintide Acetate Prescribing Information, 2005

Pramlintide Clinical Effects

-0.8

-0.6

-0.4

-0.2

0

-4

-2

0

2

4

6

8

-2

-1

0

1

***

***

***

**

*

***

******

Week 4 Week 13 Week 26Week 4 Week 13 Week 26Week 4 Week 13 Week 26

Δ Insulin Use (%)Δ A1C (%) Δ Weight (kg)

Placebo + Insulin30 or 60 μg Pramlintide TID or QID + Insulin

TYPE 1 DIABETES COMBINED PIVOTALSTYPE 1 DIABETES COMBINED PIVOTALS

ITT; Mean (SE); *P<0.05, **P<0.01, ***P<0.0001; Placebo + insulin, N = 538, Baseline A1C = 9.0% ; Pramlintide + insulin, N = 716, Baseline A1C = 8.9%Pramlintide Acetate Injection US Prescribing Information, 2005; Data on file, Amylin Pharmaceuticals, Inc.Data from: Whitehouse FW, et al. Diabetes Care 2002; 25:724-730; Ratner R, et al. Diabetic Med 2004; 21:1204-1212

Pramlintide Reduced Fasting andPostprandial Glucose

120

140

160

180

pre-bf post-bf pre-lu post-lu pre-di post-di bedtime

Glu

cose

(m

g/d

L)

Baseline6 Months

*

*

TYPE 1 DIABETESTYPE 1 DIABETES

N = 265; *P<0.5; Clinical-Practice Study: all pramlintide doses bf, breakfast; lu, lunch; di, dinnerData on file, Amylin Pharmaceuticals, Inc.

Medically Assisted Severe Hypoglycemia

Blinded Studies

Event

Rate

/Pati

ent

Year

No InsulinReduction

Insulin Reduction

InsulinReduction

Open-LabelStudy

Ψ Ψ

0.19

0.08

0.50

0.100.14

0.5

1.0

0

PlaceboPramlintide

0-3 Months

φ

Blinded Studies Open-LabelStudy

0.5

1.0

No InsulinReduction

Insulin Reduction

InsulinReduction

φ Ψ Ψ

0.24

0.15

0.27

0.20

0.04

0

>3-6 Months

PRAMLINTIDE TYPE 1 DIABETES STUDIESPRAMLINTIDE TYPE 1 DIABETES STUDIES

ITT, Indicated dose

φ No Pramlintide dose titration; Ψ Pramlintide dose titrationPramlintide Acetate Injection US Prescribing Information, 2005

Pramlintide Safety and Tolerability in Type 1 Diabetes

• Nausea:– Mostly mild-to-moderate nausea. Occurred more

frequently during initiation and then decreased with time but can increase risk of hypoglycemia.

– Nausea reduced by dose titration– Could increase risk of insulin-induced severe

hypoglycemia due to reduced food intake

• Insulin-Induced Severe Hypoglycemia:– More common in type 1 diabetes; risk reduced by appropriate

patient selection, careful patient instruction and insulin dose adjustments as stated in the Boxed Warning

Pramlintide Acetate Injection US Prescribing Information, 2005