p1 joann l. data, md, phd senior vp, regulatory affairs & quality assurance amylin...
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P1
Joann L. Data, MD, PhD
Senior VP, Regulatory Affairs & Quality AssuranceAmylin Pharmaceuticals, Inc.
Overview
P2
SYMLIN™(Pramlintide Acetate)
Amylin Pharmaceuticals, Inc.
P3
SYMLIN Injection
• Indication:
Adjunctive therapy to insulin,to improve glycemic and metabolic controlin people with type 1 or type 2 diabetes
• Administration:
Injected subcutaneously approximately15 minutes prior to a meal
• Presentations:Vials and cartridges
P4
Amylin’s Presentation
• Unmet Medical Need Kenneth Polonsky, MDChairman, Department of Medicine
Washington University
• Pramlintide Pharmacology Andrew Young, MD, PhDVP ResearchAmylin Pharmaceuticals
• Clinical Program Orville Kolterman, MDSenior VP Clinical AffairsAmylin Pharmaceuticals
• Risk/Benefit Summary Alain Baron, MDVP Clinical Research Amylin Pharmaceuticals
P5
Consultants
• Hugh E. Black, DVM, PhDToxicology ConsultantHugh E. Black and Associates, Inc.
• Wayne Colburn, PhDPharmacokinetics ConsultantMDS Pharma Services
• Richard Dickey, MDClinical ConsultantPrivate Practice,Hickory, NC
• Kerry Hafner, PhDStatistical ConsultantPRA International
• Kenneth Polonsky, MDClinical ConsultantWashington University
P6
Kenneth Polonsky, MD
Adolphus Busch Professor of MedicineChairman, Department of Medicine
Washington University School of Medicine
Unmet Medical Need
P7
Type 1
Insulin therapy
1920 20001900 1950
A Century of Diabetes Care
Pump thera
py
Human insulin
Insulin analogs
NPH insulin
Oral Agents
Type 2
Insulin therapy
1920 20001900 1950
P8
Insulin Therapy NecessaryWhen -Cell Fails
• Type 1 diabetes - -cell failure at outset– Insulin dependent
• Type 2 diabetes - Gradual -cell deterioration– Diet and oral agents early stages of disease– Late-stage disease, insulin therapy necessary
P9
Diabetes 1996,45:1289-1298 Lancet 1998;352:837-853
DCCT (Type 1)
Retinopathy
16
12
8
4
05 6 7 8 9 10 11 12
HbA1c (%)
Ra
te/1
00
Pa
tie
nt
Ye
ars
UKPDS (Type 2)
HbA1c (%)
Inc
ide
nc
e/1
00
Pa
tie
nt
Ye
ars 8
6
4
2
05 6 7 8 9 10 11
Retinopathy
Lessons from the DCCT and UKPDS:Continuous Relationship Between Glycemia
and Long-Term Complications
No threshold effect – the lower the better
P10
8.8
8.1
7.2
7.7
4
6
8
10
Hb
A1
c (
%)
0
6
7
8
0 2 4 6 8 10 yrs
Hb
A1
c (
%)
UKPDS (Type 2),Insulin Group
Normal
Baseline
0 6.5 + 4 + 6 yrs
DCCT EDIC
DCCT (Type 1)
Lessons from the DCCT and UKPDS:Sustained Intensification of Therapy is Difficult
UK Prospective Diabetes Study Group (UKPDS) 33:Lancet. 1998;352:837–853.
DCCT/EDIC Study Group, Diabetes 2001 (Suppl. 1) 41: A63.
P11
Insulin Therapy and Glycemic Control in Young, Insulin-Treated Patients
The Wisconsin Longitudinal Study
Klein et al, Diabetes Care 1996, 19: 744-750
20%
60%
80%
100%
Number of Injections
40%
0%
0 4 10 yrs
20%
60%
80%
100%
Type of Insulin
40%
0%
0 4 10 yrs
HbA1c
0 4 10 yrs
2%
6%
8%
10%
4%
0%
Short ActingShort and Long ActingLong Acting
3 or more21
P12
Lessons from the DCCT and UKPDS:Intervention Works, but is Difficult to Achieve
Population data shows inadequate glycemic control in diabetes patients in the US
ADA:recommended target
Upper limitof normal range
ADA:intensification advised
7%
8%
9%
6%
Hb
A1c
10%
8.8% El-Kebbi IM, Arch Intern Med 161: 1295-301 20019.1% Klein et al, Diabetes Care 19: 744-750 1996
9.6% Type 2 Patients, Hiss et al, ADA 20019.8% Type 1 Patients, Hiss et al, ADA 2001
P13
Our Ability to Achieve Tight Glycemic Control with Insulin Therapy is Limited by:
• Hypoglycemia
• Weight Gain
• Postprandial hyperglycemia
P14
Barriers to Achieving Glycemic Targets with Insulin in Type 1 Diabetes: Severe Hypoglycemia
DCCT Research Group, Diabetes 1997;46:271-286
HbA1c (%) During Study
100
80
60
40
20
0
5 6 7 8 9 10 11 12 13 14
Rat
e/10
0 P
atie
nt
Yea
rs
Conventional
Intensified
Intensified regimens result in 3- to 4-fold higher severe hypoglycemia event ratesthan conventional regimens
P15
Barriers to Achieving Glycemic Targets with Insulin in Type 2 Diabetes: Hypoglycemia
Adjunct therapy to Insulin
Pioglitazone• Hypoglycemia incidence
– Pbo
– 15mg QD
– 30mg QD
Acarbose• Hypoglycemia incidence
– Pbo
– 25-100mg TID
Lancet 352: 837-853, 1998
5
4
3
2
1
0
0 3 6 9 12 15
Intensified
Conventional
Years from Randomization
Maj
or
Ep
iso
des
In
cid
ence
(%
)
Intensification with Insulin
Pioglitazone NDA, 1998Kelley et al, Diabetes Care 21: 2056-61, 1998
5%
8%
15%
22%
29%
P16
DCCT (Type 1) UKPDS (Type 2)
Intensified Insulin TherapyProduces Weight Gain
Diabetes Care 1988;11:567-573JAMA 1998;280:140-146 Lancet 1998; 352:837-853
Conventional
Intensified
30
25
20
15
10
5
0
-5
1 2 3 4
Quartile of Weight Gain
Mea
n c
han
ge
in w
eig
ht
(kg
)
0 3 6 9 12 15
7.5
5.0
2.5
0.0
Intensified
ConventionalC
han
ge
in
wei
gh
t (k
g)
Years from Randomization
P17
Impact of Weight Gainon Cardiovascular Risk Factors
Type 1 Patients on IIT (n=582), Stratified by Weight Change
1st
Quartile2nd
Quartile3rd
Quartile4th
Quartile
120
118
116
114
112
110
A Systolic BP
mm
Hg
1st
Quartile2nd
Quartile3rd
Quartile4th
Quartile
80
78
76
74
72
70
B Diastolic BP
mm
Hg
1st
Quartile2nd
Quartile3rd
Quartile4th
Quartile
90
85
80
75
70
65
C Triglycerides
mg
/dL
1st
Quartile2nd
Quartile3rd
Quartile4th
Quartile
D Total Cholesterol
mg
/dL
195
190
185
180
175
170
Purnell J, JAMA 1998;280:140-146
P18Polonsky KS, New Engl J Med, 1988; 318: 1231-1239.
Glucose Lowering Efficacy:Importance of Postprandial Hyperglycemia
400
300
200
100
0600 1000 1400 1800 2200 0200 0600
Glu
cose
(m
g/d
L)
DIABETIC
CONTROL
P19
Target Range
0
50
100
150
200
250
300
350
400
Glu
cose
(m
g/d
L)
Sensor Measurement
Insulin Bolus
Fingerstick Measurement
Daily Log and Sensor Data (24 hrs)
8AM 12 Noon 7PM Midnight
Age: 44 yearsHbA1c 7.1%
Type 1 Patient
P20
Current Opportunity toAchieve Glycemic Goals
• Control Postprandial Glucose
• Without Weight Gain
• Without Increasing Hypoglycemia
P21
Andrew Young, MD PhD
Vice President, ResearchAmylin Pharmaceuticals, Inc.
Pramlintide Pharmacology
P22
Pramlintide Pharmacology
• Comparison of amylin and pramlintide molecules• Insulin, glucagon and amylin abnormalities
in diabetes• Glucose fluxes controlled by amylin/pramlintide• “Glucose-dependence” of amylin/pramlintide action
~ 1700 scientific communications
P23
• 37-amino acid peptide• Located almost entirely in -cells• Co-secreted with insulin during meals • Receptor characterized in CNS
Healthy subjectsn = 6
Plasma insulin
(pM)
Plasma amylin (pM)
30
25
20
15
10
57 am Midnight5 pm12 noon
Time
Amylin
Insulin
600
400
200
0
Adapted from Koda JE, et al. Diabetes 1995.
Amylin: a Neuroendocrine Hormone
P24
Amylin Binding/Receptors in Rat Brain
nucleusaccumbens
areapostrema
dorsalraphe
P25
Hormonal Disturbances in Diabetes
• Insulin Deficiency
• Amylin Deficiency
• Glucagon ExcessUnger et al., J Clin. Invest. 1970Dobbs et al., Science 1975.
Fineman et al., Diabetologia 1996Data on file
Insulin-usingType 2
Time after liquid meal (min)
0
5
10
15
20
-30 0 30 60 90 120 150 180
Non-diabetic
Type 1
Plasmaamylin(pM)
P26
Pramlintide: an Analog of Amylin
• Human amylin not pharmaceutically practical• Pramlintide designed to be non-aggregating,
soluble, stable• Full spectrum of activity, equipotent, similar
kinetics
P27
Three Fluxes Control Blood Glucose
Glucagon Amylin
Insulin
--
+
+
-
Meal
Glucose
P28
Pramlintide Smoothes Glucose Profiles After Meals in Type 1 Diabetic Humans
0 30 60 90 120 150 180
-50
-25
0
25
50
75
100
125
Minutes after Sustacal
Ch
ang
e i
n g
luco
se (
mg
/dL
)Placebo
10 µg
30 µg
60 µg
100 µg
300 µg
P29
Glucoregulatory Actions of Amylin
*
*
* In man
GlucagonSecretion
Amylin
Glucose
Insulin
Satiety
Gastric Emptying
Digestion
P30
Pramlintide Suppresses Postprandial Glucagon Secretion
Pram 30 g + Ins (N=14)
P<0.05, incremental AUC
Placebo + Ins (N=20)
Mea
n c
han
ge
in
pla
sma
glu
cag
on
(p
g/m
L)
0
10
20
30
0 30 60 90 120 150 180
Sustacal
60
0
20
40
0 60 120 180 240
Insulin
Sustacal
Infusion
p=0.005
Mea
n c
han
ge
in
pla
sma
glu
cag
on
(p
g/m
L)
Injection
Type 1 diabetes, SC injection Type 2 diabetes, IV infusion
P31
Amylin Inhibits Nutrient-Stimulated,But Not Hypoglycemia-Stimulated
Glucagon Secretion in Rats
Glucose 6mM (clamped) 2mM (hypo)
-60 60 180 2400 120
0
100
200
300
SalineAmylin
5001000
L-Arginine
Minutes
Glucagon(pM)
Silvestre et al., Am. J. Physiol 2001.
P32
Pramlintide Does Not Affect Defenses Against Hypoglycemia in Humans
• Pramlintide does not suppress secretion of:– Glucagon– Growth Hormone– Cortisol– Epinephrine– Norepinephrine
• Pramlintide does not impede glucose responseto glucagon intervention
Study AP93-04, AP93-08
P33
Glucoregulatory Actions of Amylin
* In man
Amylin
Glucose
Insulin
Digestion
GlucagonSecretion Satiety
Gastric Emptying
*
*
P34
Gastrichalf-
emptying time
(hours)
* p < 0.004 vs. placebo
0
1
2
3
4
90 µg60 µg30 µgPlacebo
* **
Single SC doses (N = 11, crossover);Tc-99m labelled pancake;solid component measured
~1 hour delay
Pramlintide Slows Gastric Emptyingin Humans with Type 1 Diabetes
Kong et al. Diabetologia 1998.
P35
Enables oral rescue from hypoglycemia
02468
0%
20%
40%
60%
80%
100%
Saline
Amylin 1µg sc
Plasma Glucose (mM)
Gastriccontentspresent
after20 minutes
Gastric Actions of AmylinOver-ridden by Hypoglycemia in Rats
P36
Amylin-Sensitive Neurons in Area Postrema are Almost All Glucose-Sensitive
0 60 120 180Minutes
0
2
4
12
Spikesper sec
2 4 6Glucose mM
Amylin 10nM
P37
Summary: Glucoregulatory Actionsof Amylin/Pramlintide
• Inhibits nutrient stimulated glucagon secretion
• Regulates nutrient uptake from the meal
• Glucose-lowering actions over-riddenduring hypoglycemia
P38
Summary: Rationale for Pramlintide
• Pramlintide replaces absent amylin
• Pramlintide restores control of glucose influx Complements insulin control of glucose efflux
P39
Orville G. Kolterman, MD
Senior Vice President, Clinical Affairs,Amylin Pharmaceuticals, Inc.
Adjunct Professor of Medicine University of California, San Diego
Clinical Program
P40
Pramlintide Indication
Adjunctive therapy to insulin,
to improve glycemic and metabolic control
in people with type 1 or type 2 diabetes
P41
ß-cellfunction
Disease Progression
DietExercise
PLUSOral agent
Normal
Absent
Type 2PLUSCombinationOral agents
Type 1
Pramlintide Population
Treatment population PLUSInsulin
P42
Pramlintide Therapy
Program Overview• Pharmacodynamic Review• Type 2 Diabetes
• Efficacy• Safety
• Type 1 Diabetes• Efficacy• Safety
P43
TOTAL PATIENTS
Number of Patients Includedin Pramlintide Database
Clin Pharm / Others
Total Patient-Yr Exposure
TOTAL PATIENTS
Type 2 Diabetes-Long-term, controlled
Type 1 Diabetes-Long-term, controlled
Pramlintide
4493
1011
2727
1512(1273)
1970(1179)
Placebo
1504
453
697
470(420)
581(538)
P44
4493
0
500
1000
1500
2000
2500
3000
3500
Duration of Exposure
1 Dose
2109
6 Months
1350
1 Year
261
2 Years
4000
4500
Number of Subjects
Duration of Exposure to Pramlintide All Studies, All Doses
P45
Population DemographicsLong-Term, Controlled Studies
Age (mean years)
Duration of diabetes (mean yrs)
HbA1c (mean %)
BMI (mean kg/m2)
Type 1Studies
Type 2Studies
40
17
8.9
26
57
12
9.2
32
P46
% Patients
Type 1 Diabetes
(n=1179)
Type 2 Diabetes
(n=1273)
Antibiotics 35.3 39.4
CV Medications 32.0 65.5
Lipid Lowering Agents 6.4 24.5
Oral Hypoglycemic Agents 0.3 21.0
Prokinetic Agents 1.2 1.8
Total 56.3 82.2
Concomitant Medication Use
Sulfonylureas
Glitazones
Biguanides
Glucosidase Inh.
13.2
0.5
11.9
0.2
21.0
P47
Pramlintide as Adjunctive Therapy to Insulin in Type 1 and Type 2 Diabetes Results in:
• Further improvement in glycemic control– Postprandial glucose
– HbA1c
• No increase in insulin use• Weight loss
P48
Pramlintide Therapy
• Program OverviewPharmacodynamic Review• Type 2 Diabetes
– Efficacy– Safety
• Type 1 Diabetes– Efficacy– Safety
P49
Pramlintide Pharmacokinetic ProfileType 1 and Type 2 Diabetes
Type 1 Diabetes
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
0 1 2 3 4 5
Pla
sm
a P
ram
lin
tid
e C
on
ce
ntr
ati
on
(p
mo
l/L
)
1 x 30 µg Pramlintide 1 x 60 µg Pramlintide1 x 90 µg Pramlintide
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
0 1 2 3 4 5
Pla
sm
a P
ram
lin
tid
e C
on
ce
ntr
ati
on
(p
mo
l/L
)
Type 2 Diabetes
Hours from Initial Dosing
1 x 60 µg Pramlintide1 x 90 µg Pramlintide
1 x 120 µg Pramlintide
P50
Plasma Pramlintide
Pla
sma
Pra
mli
nti
de
(pM
) N=15
0 30 60 90 120 150 180
0
25
50
Time (min)
Kolterman et al., Diabetologia 1996.
Plasma Glucose
Pla
sma
Glu
cose
(m
g/d
L)
100
150
200
250
300
0 30 60 90 120 150 180
Time (min)
Insulin only
Pram (30 µg)+ Insulin
Meal
Addition of Pramlintide to Regular Insulin TherapyImproves Postprandial Glucose Control
Mean (SE)
Type 1 Diabetes
P51
Time (minutes)
-30 0 30 60 120 270 360180 240 300 420
Plasma Glucose (mg/dL)
90
120
150
240
180
210
270
Pramlintide 30 µg QID+ Insulin (n=14)
Placebo + Insulin (n=14)Study Drug +
Insulin
Study Drug +Insulin
LunchBreakfast
p=0.001 post-breakfastp=0.02 post-lunch
137-107
Preprandial Addition of Pramlintide Improves Postprandial Glucose Control
Mean (SE)
Type 1 Diabetes, 28 Day Study
P52
Pramlintide Reduces Postprandial Glucose Concentrations in a Dose-Related Manner
0 30 60 90 120 150 180
-50
-25
0
25
50
75
100
125
Minutes after Sustacal
Ch
ang
e i
n G
luco
se (
mg
/dL
) Placebo
10 µg
30 µg
60 µg
100 µg
300 µg
Type 1 Diabetes
AP93-08, 137-104, 137-105
P53
0
10
20
30
40
50
60
70
80
90
100
Incid
ence o
f Nau
sea (%)
Bar = Nausea Incidence
Pramlintide Dose-Relationships
-4000
-2000
0
2000
4000
6000
8000
10000
12000
14000
Mea
n G
luco
se In
crem
enta
l AU
C
(m
g•m
in/d
L, 0
-180
min
)
Dose (µg Pramlintide)
Placebon=107
10n=43
30n=189
60n=42
100n=65
300n=21
AP93-08, 137-104, 137-105
Type 1 Diabetes
Line = Mean Glucose AUC
Dose Response Test: P = 0.012
P54
Pramlintide Dose-RelationshipsM
ean
Ch
ang
e in
% H
bA
1cF
rom
Bas
elin
e
Line = Mean HbA1c Dose (µg) Pramlintide
Placebon=99
30n=90
75n=102
150n=90
0
10
20
30
40
50
60
70
80
90
100
Incid
ence o
f Nau
sea (%)
Bar = Nausea Incidence
Type 2 Diabetes, Week 13
-1.0
-0.8
-0.6
-0.7
-0.9
-1.1
P55
Doses Selected for Phase 3 Studies
• Type 2 diabetes range: 30 to 150 µg • Type 1 diabetes range: 30 to 90 µg
P56
Phase 3 Clinical Trials
• Demonstration of efficacy• Assessment of safety • Guidance for clinical use
P57
Study Design Considerations
• No precedent for efficacy studiesin insulin-treated subjects
• DCCT established HbA1c as surrogateendpoint for glycemic control
• On-going debate regarding “threshold effect”
• Ancillary metabolic effects (weight, insulin use, lipid profile) not fully appreciated
P58
General Approach to PramlintidePhase 3 Clinical Studies
• All subjects were treated with insulin
• All studies employed an “add-on” design
– Pramlintide or placebo was addedto existing therapies
– Oral hypoglycemic agents wereto be unchanged
• Sulfonylurea
• Metformin
P59
Approaches to Insulin Management
Clinical Trial Setting• Insulin should ideally remain constant
to isolate effect of “add-on” drug • Changes in insulin use during the
study period confound data interpretation
Clinical Practice Setting• Involves frequent changes in insulin regimens
– Patient safety (hypoglycemia)– Pursuit of glycemic targets
P60
Insulin Use in PramlintidePhase 3 Clinical Studies
• Four studies Consistent insulin dosing encouraged
• Two studies No constraints on insulin dosing
• Allowed changes for patient safety
• Patients were not discontinued due to changes in insulin regimen
• Analysis plan pre-defined “stable insulin” subgroup
– Total daily dose at baseline ± 10%
– Isolates “true” drug effect
P61
Phase 3 Study DesignType 2 and Type 1 Diabetes
• Multicenter, randomized, placebo-controlled• Primary endpoint
– HbA1c, week 26 or 52
• Secondary endpoints– Weight– Insulin use– Safety parameters
P62
Pramlintide Therapy
• Program Overview• Pharmacodynamic Review Type 2 Diabetes
Efficacy• Safety
• Type 1 Diabetes• Efficacy• Safety
P63
Type 2 Diabetes Phase 3 Program
Metabolic Stability
137-123PBO, Pram 90 BID, 90 TID or 120 BID
N = 499
137-122PBO, Pram 60 TID, 90 BID or 120 BID
N = 656
Endpoint Assessments (Week) 40 13 392620 52
RandomizationPlaceboLead-In
137-111 PBO, Pram* 30, 75, or 150 TIDN = 538
* pH=4.7; lower bioavailabity, 150 µg 120 µg
P64
Summary of Pramlintide EffectsType 2, Recommended Dose
HbA1c
0102030405060708090
100
0-4 4-26 26-52
Time (Weeks)
Incidence(%)
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0 13 26 39 52
Mea
n (
SE
) C
han
ge
in H
bA
1c
0
1
2
3
4
5
0-4 4-26 26-52
Time (Weeks)
Event Rate/
SubjectYear
Time (Weeks)
Overall Nausea Severe Hypoglycemia
Placebo + Insulin (n=207) *Pramlintide + Insulin (n=222) *
* Evaluable Population
P65
90BID+ Ins
n=171
n=161
Pbo +Insulin
P=0.002
*
120BID+ Ins
n=166
137-122 (US)
Pramlintide Phase 3 Studies Type 2 DiabetesHbA1c Effect for Total Population (ITT, 6 months)
Me
an
(S
E)
H
bA
1c (
%)
0
-0.4
-0.3
-0.2
-0.1
-0.5
-0.6
-0.7
-0.8
137-123 (Eur)90TID+ Ins
n=129
90BID+ Ins
n=121
n=123
Pbo +Insulin
120BID+ Ins
n=126
P=0.029
Dosage Recommendation: 120 µg given 2-3 times/day
150TID+ Ins
n=144
P=0.010
*
75TID+ Ins
n=136
30TID+ Ins
n=122
Pbo +Insulin
n=136
137-111 (US)
P=0.004
*
P66
Addition of Pramlintide to Insulin ReducesHbA1c in Type 2 Diabetes
Stable InsulinITT
Placebo + Insulin
Pramlintide 120 BID + Insulin 137-122
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
Mea
n H
bA
1c C
han
ge
Fro
m B
asel
ine
(%)
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0 13 26 39 52
WeekWeek
0 13 26 39 52
Mea
n H
bA
1c C
han
ge
Fro
m B
asel
ine
(%)
P=0.063
P=0.007
P<0.001
P<0.001
Placebo + Insulin n=161Pramlintide 120 BID + Insulin n=166
Placebo + Insulin n=55Pramlintide 120 BID + Insulin n=70
P67
Pramlintide Therapy Results in Greater Reduction in HbA1c Than Insulin Alone in Type 2 Diabetes,
Recommended Dose (Week 26)
0
10
20
30
40
50
60
70
80
90
100
Cu
mu
lati
ve P
erce
nt C
um
ulative P
ercent
100
90
80
70
60
50
40
30
20
10
0
-2 -1 0 1 2
Change in HbA 1C from Baseline
Placebo Pramlintide 120 BID
Worse Improved
-1.5 0.5 0.5 1.5
P68
Pramlintide FacilitatesAchievement of ADA Targets
Type 2 Diabetes, Week 26
Placebo + Insulin
Pramlintide
120 BID/150 TID + Insulin
Achieved 8%or Less
Achieved 7%or Less
21%
2%
35%
8%
Pooled data
P69
Weight EffectType 2 Diabetes, Week 26
-5
-4
-3
-2
-1
0
1
2
3
Mea
n (
SE
)
We
igh
t (l
b)
n=97
n=90
P=0.0029
*n=88
P<0.0001
*
n=100
P=0.0005
*
150TID+ Ins
Pbo +Insulin
75TID+ Ins
30TID+ Ins
137-111 (US)
n=97
90BID+ Ins
n=103
P=0.0194
*
Pbo +Insulin
120BID+ Ins
137-123 (Eur)
90TID+ Ins
n=98
P=0.0002
*
n=100
P<0.0001
*
90BID+ Ins
Pbo +Insulin
120BID+ Ins
137-122 (US)
n=131
n=108
n=121P=0.0094
*P<0.0001
*
P70
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
Change in % HbA1c
Week 4 Week 13 Week 26
Change in Weight (lb)
-3
-2
-1
0
1
2
3
4
5
6
Week 4 Week 13 Week 26
Change in Insulin Use (%)
-4
-3
-2
-1
0
1
2
Week 4 Week 13 Week 26
Pramlintide Therapy Offers Unique Metabolic Benefits in Type 2 Diabetes
All Patients, Recommended Dose
Placebo + Insulin (N=284)
Pramlintide Recommended Dose + Insulin (N=292)
Baseline: 9.3 9.1
P71
Pramlintide Therapy
• Program Overview• Pharmacodynamic Review• Type 2 Diabetes
• EfficacySafety
• Type 1 Diabetes• Efficacy• Safety
P72
TOTAL PATIENTS
Number of Patients Includedin Pramlintide Database
Clin Pharm / Others
Total Patient-Yr Exposure
TOTAL PATIENTS
Type 2 Diabetes-Long-term, controlled
Type 1 Diabetes-Long-term, controlled
Pramlintide
4493
1011
2727
1512(1273)
1970(1179)
Placebo
1504
453
697
470(420)
581(538)
P73
Placebo
Cardiac
Sudden Death
Total
4 (0.75%)
1 (0.19%)
5 (0.94%)
(n = 532)
No Increase in Mortality Observedin Type 2 Diabetes Studies
• 10 deaths occurred among 2195 unique subjectsin type 2 diabetes studies
• None classified as drug related
Pramlintide
Cardiac
Total
5 (0.30%)
5 (0.30%)
(n = 1663)
P74
Adverse Event Profile for Type 2 DiabetesFrequent TEAEs (% of Subjects), Overall Incidence > 5%,
Excluding Hypoglycemia
% of SubjectsPlacebo
N=420
Pramlintide
N=1273
Nausea 14 (1 severe) 24 (2 severe)
Anorexia 3 8
Vomiting 5 7
Abdominal pain 6 8
Fatigue 4 7
Dizziness 4 6
Dyspepsia 3 6
P75
Vision/Retinal Disorder Adverse Events
• One study (137-111) had an apparent increasein incidence of retinal disorder in the 150 µg treatment arm compared with placebo
• No apparent pramlintide-related increase in incidence of retinal disorder or other vision disorders at doses of 75 µg TID or 120 µg BID
• No safety concern
P76
Placebo Pramlintide
Body as a Whole 3% 2%
Heart Rate & Rhythm 1% < 1%
Type 2
Serious Treatment-Emergent Adverse Events Were Similar (1% of Subjects)
Body System:
Central & PeripheralNervous System
<1% 1%
2% 1%Neoplasm
Vascular (extra-cardiac) 1% 2%
Cardiac 4% 3%
Metabolic & Nutritional 1% 2%
1% < 1%Platelets, Bleeding & Clotting
Gastrointestinal 1% 2%
Events different between pramlintide and placebo
P77
Severe Hypoglycemia (DCCT Definition)for Type 2 Diabetes Studies
Number and incidenceof patients with at least1 hypoglycemia episode
Patient exposure (years)
Number of hypoglycemicevents
Placebo
17 (6%)
188
0.21
40
Pramlintide
76 (9%)
587
0.24
139
Number of hypoglycemicevents per one year ofpatient time
137-122, 137-123 Combined (ITT)
P78
Severe Hypoglycemia Event RatesType 2 Diabetes
All Pramlintide vs. All Placebo
0.20.5
0.2 0.3 0.30.1
0
1
2
3
4
5
Mean (SE)
Event
Rate Per
Subject
Year
Pram + InsPbo + Ins
n=284 n=871 n=820n=267
Pram + InsPbo + Ins Pram + InsPbo + Ins
n=576
Weeks 0-4 Weeks 4-26 Weeks 26-52
n=175
P79
Other Safety ObservationsType 2 Diabetes
• No evidence of:– Serious events that are unusual in the absence of
drug therapy– Cardiac toxicity– Hepatic toxicity– Renal toxicity
• No increase in frequency of clinically significant:– Lipid abnormalities– ECG changes– Changes in vital signs
• Systolic blood pressure• Diastolic blood pressure
– Laboratory abnormalities
P80
Pramlintide is Efficacious and Safein Type 2 Diabetes
• Improves glycemic control
• No increase in insulin use
• Weight loss
• No safety issues
• Dosage recommendation: 120 µg given 2-3 times/day before meals
P81
Pramlintide Therapy
• Program Overview• Pharmacodynamic Review• Type 2 Diabetes
• Efficacy• Safety
• Type 1 DiabetesEfficacy• Safety
P82
Type 1 Diabetes Phase 3 Program
Endpoint Assessments (Week) 40 13 392620 52
RandomizationPlacebo Lead-In
137-112PBO, Pram 30 QID Pram 30 QID / 60 QID
Re-randomization
N = 480
137-121PBO, Pram 60 TID, 60 QID or 90 TID
N = 651
137-117PBO, Pram 60 TID, 90 BID or 90 TID
N = 586
MetabolicStability
P83
Summary of Pramlintide EffectsType 1, Recommended Dose
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0 13 26 39 52Me
an
(S
E)
Ch
an
ge
in
Hb
A1
c HbA1c
Overall Nausea Severe Hypoglycemia
0
1
2
3
4
5
0-4 4-26 26-52
Time (Weeks)
EventRate/
SubjectYear
0102030405060708090
100
0-4 4-26 26-52
Time (Weeks)
Incidence(%)
Placebo + Insulin (n=393)*Pramlintide + Insulin (496)*
Time (Weeks)
* Evaluable Population
P84
137-121 (US)
n=154
Pbo +Insulin
60TID+ Ins
n=164
P=0.012
*
n=161
60QID+ Ins
P=0.013
*
-0.2
0
-0.4
-0.3
-0.1
-0.5Me
an
(S
E)
H
bA
1c (
%)
-0.6
+0.1
Pramlintide Phase 3 Studies Type 1 DiabetesHbA1c Effect for Total Population (ITT, 6 months)
137-112 (US)
30/60QID + Ins
n=243
n=234
Pbo +Insulin
P<0.001
*
137-117 (Eur)
60TID+ Ins
n=148
n=147
Pbo +Insulin
90TID+ Ins
n=147
90BID+ Ins
n=144
P=0.007
Dosage Recommendation: Initiate at 30 µg 3-4 times/day Maintenance 30 or 60 µg 3-4 times/day
P85
Addition of Pramlintide to Insulin ReducesHbA1c in Type 1 Diabetes
Stable InsulinITT
Placebo + Insulin
Pram 60 TID + Insulin
Pram 60 QID + Insulin137-121
Mean (SE)
Placebo + Insulin n=154Pram 60 TID + Insulin n=164Pram 60 QID + Insulin n=161
P=0.011
P=0.001
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0 13 26 39 52
Weeks
P=0.012
P=0.012
Me
an
Hb
A1c
Ch
an
ge
fro
m B
as
eli
ne
(%
)
Weeks
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
P=0.015
P=0.003
P=0.007
P=0.017
Hb
A1c
Ch
an
ge
fro
m B
as
eli
ne
(%
)
0 13 26 39 52
Placebo + Insulin n=36Pram 60 TID + Insulin n=30Pram 60 QID + Insulin n=30
P86
Change in HbA 1C (%) From BaselinePlacebo Pramlintide 30/60 QID Pramlintide 60 TID Pramlintide 60 QID
Pramlintide Therapy Results in Greater Reduction in HbA1c Than Insulin Alone in Type 1 Diabetes,
Recommended Doses (Week 26)
0
10
20
30
40
50
60
70
80
90
100
Cu
mu
lati
ve P
erce
nt
Cu
mu
lative Percen
t
100
90
80
70
60
50
40
30
20
10
0
Worse Improved
-2 -1 0 1 2-1.5 0.5 0.5 1.5
P87
Pramlintide FacilitatesAchievement of ADA Targets
Type 1 Diabetes, Week 26
Pooled data
Placebo + Insulin
Pramlintide
Recommended Doses
Achieved 8%or Less
Achieved 7%or Less
28%
7%
47%
14%
P88
Weight Effect Type 1 Diabetes, Week 26
-5
-4
-3
-2
-1
0
1
2
3
Mea
n (
SE
)
We
igh
t (l
b)
Pbo +Insulin
n=168
30/60QID + Ins
n=174
P<0.0001
*
137-112 (US)
Pbo +Insulin
60TID+ Ins
n=99
P<0.0001
*
60QID+ Ins
n=106
P<0.0001
*
137-121 (US)
n=104
Pbo +Insulin
n=119
60TID+ Ins
n=113
P<0.0001
*
90TID+ Ins
n=90
P<0.0001
*
90BID+ Ins
P=0.0035
*
137-117 (Eur)
n=86
P89
Pramlintide Therapy Offers Unique Metabolic Benefits in Type 1 Diabetes
All Patients, Recommended Doses in Type 1
Change in % HbA1c
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0Week 4 Week 13 Week 26
Change in Weight (lb)
-3
-2
-1
0
1
2
3
4
5
6
7Week 4 Week 13 Week 26
Change in Insulin Use (%)
-3.0-2.5-2.0-1.5-1.0-0.5
00.51.01.52.02.5
Week 4 Week 13 Week 26
Placebo + Insulin (N=538)
Pramlintide Recommended Doses + Insulin (N=716)
Baseline: 9.0 8.9
P90
Pramlintide Benefits are Seen in Patients with Type 1 Diabetes Targeting Optimal
Glycemic Control
0
2
4
6
Ch
an
ge
in
In
su
lin
Us
e (
%) Insulin Use
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (Weeks)
7.2
7.4
7.6
7.8
8
Pramlintide (n=243)
Placebo (n=173)
Ch
an
ge
in
We
igh
t (l
b)
-3
-2
-1
0
1
Weight
MeanHbA1C
(%)
P91
Pramlintide Therapy
• Program Overview• Pharmacodynamic Review• Type 2 Diabetes
• Efficacy• Safety
• Type 1 Diabetes• EfficacySafety
P92
TOTAL PATIENTS
Number of Patients Includedin Pramlintide Database
Clin Pharm / Others
Total Patient-Yr Exposure
TOTAL PATIENTS
Type 2 Diabetes-Long-term, controlled
Type 1 Diabetes-Long-term, controlled
Pramlintide
4493
1011
2727
1512(1273)
1970(1179)
Placebo
1504
453
697
470(420)
581(538)
P93
Placebo Pramlintide
Cardiac
Total
2 (0.22%)
2 (0.22%)
Cardiac
Inflicted Injury
Alcohol
Total
2 (0.08%)
1 (0.04%)
1 (0.04%)
5 (0.19%)
(n = 904) (n = 2573)
No Increase in Mortality Observedin Type 1 Diabetes Studies
• 7 deaths occurred among 3477 unique subjects• 1 classified as “possibly drug related”
Multi-Organ Failure 1 (0.04%)
P94
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
An
nu
al E
ven
t R
ate
per
Pat
ien
t-Y
ear
(±95
% C
I)
Motor Vehicle Accidents/Injuries,All and Hypoglycemia-Related
Type 1 Diabetes, Annual Event Rate per Patient-Year
Placebo(2 of 904 pts)
Hypo-Related
0.10
0.00Pramlintide(28 of 2573 pts)
All
Placebo(7 of 904 pts)
Pramlintide(17 of 2573 pts)
p=0.13p=0.56
P95
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
Other Accidents/Injuries (Non-MVA),All and Hypoglycemia-Related
Type 1 Diabetes, Annual Event Rate per Patient-Year
(10/2573 pts)(2 of 904 pts)(197/2573 pts)(53/904 pts)
Hypo-Related
Accidents/Injuries
AllAccidents/Injuries
An
nu
al E
ven
t R
ate
per
Pat
ien
t-Y
ear
(±95
% C
I)
PlaceboPramlintidePlacebo Pramlintide
p=1.00p=0.59
P96
Adverse Event Profile for Type 1 DiabetesFrequent TEAEs (% of Subjects), Overall Incidence > 5%,
Excluding Hypoglycemia
Nausea
Anorexia
Vomiting
Abdominal pain
Fatigue
Dizziness
Dyspepsia
PlaceboN=538
17 (1 severe)
2
7
7
4
4
3
PramlintideN=1179
51 (7 severe)
18
13
8
7
4
4
P97
Most Nausea is Mild to ModeratePramlintide-Treated Type 1 Patients
in Long-Term Controlled Trials
No nausea49%
Mild22%
Moderate22%
Severe7%
P98
Nausea is Dose DependentType 1 Diabetes Long-Term Controlled Studies
Pramlintide Dose
Inci
den
ce
of
Na
use
a (%
)
0
10
20
30
40
50
60
0 (Placebo) 30/60 µg 60 µg 90 µg
70
80
90
100
P99
Nausea Dissipates Over TimeType 1 Diabetes, Long-Term Controlled Studies
Incidence
(%)
ITT
0
10
20
30
40
Weeks 0 to 4 Weeks 4 to 26 Weeks 26 to 52
Placebo + Insulin
Pramlintide + Insulin
50
60
70
80
90
100
P100
Serious Treatment-EmergentAdverse Events (1% of Subjects)
Placebo Pramlintide
Body as a Whole 1% 2%
Gastrointestinal 2% 1%
Cardiac 1% <1%
Type 1Body System:
Central & PeripheralNervous System
0% 1%
1% <1%Respiratory
1% <1%Urinary
Cardiovascular 1% <1%
1% <1%Resistance Mechanism
Metabolic & Nutritional 6% 10%
Events different between pramlintide and placebo
P101
Assessment of Severe Hypoglycemiain Long-Term Controlled Trials
• Objective endpoints employed (DCCT)
– Requiring the assistance of another individual (including aid in ingestion of oral carbohydrate)
-or-– Requiring the administration of glucagon
injection or intravenous glucose
• Sponsor’s intent was to have severe hypoglycemia reported as SeriousAdverse Events
P102
Severe Hypoglycemia Annual Event Rate Type 1 Diabetes
1.1 1.1
0
1
2
3
4
5
Mean (SE)
Event
Rate per
Subject
Year
Pram + InsPbo + Insulinn=538 n=1179
P103
Severe Hypoglycemia Annual Event Rate Type 1 Diabetes Excluding Outlier
1.1 1.1
0
1
2
3
4
5
Mean (SE)
Event
Rate per
Subject
Year
Pram + InsPbo + Insulinn=538 n=1179
P104
Placebo +Insulinn=502
Severe Hypoglycemia Annual Event Rate over TimeType 1 Diabetes
1.6
3.2
1.1 1.0 1.00.6
0
1
2
3
4
5
Mean (SE)Event
Rate perSubject
Year
Pramlintide + Insulinn=1179
Placebo +Insulinn=538
Pramlintide + Insulinn=1025
Pramlintide + Insulin
n=641
Placebo +Insulinn=359
Weeks 0-4 Weeks 4-26 Weeks 26-52
P105
Severe Hypoglycemia Annual Event Rate by DoseType 1 Diabetes
Weeks 0-45
4
3
2
1
0Placebo
+ Ins
Pram 30 QID
+ Ins
Pram 60 TID
+ Ins
Pram 60 QID
+ Ins
Pram 90 BID
+ Ins
Pram 90 TID
+ Ins
Mean (SE)Event
Rate PerSubject
Year
P106
Risk for Severe HypoglycemiaDecreases over TimeType 1 Diabetes, All Patients
Ris
k
0.00
0.01
0.02
0.03
0.04
0.05
0.06
Weeks
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
Placebo + Insulin
Pramlintide + Insulin
RT O’Neill Drug Information Journal; 21: 9-20, 1987.
P107
Risk for Severe HypoglycemiaDecreases over Time
Type 1 Diabetes, 30 µg QID
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
Week
Ris
k
Placebo
Pramlintide
RT O’Neill Drug Information Journal; 21: 9-20, 1987.
P108
Pramlintide AloneDoes Not Cause Hypoglycemia
Normal volunteers did not becomehypoglycemic following 10,000 µg dose
80x maximum recommended dose
P109
Pramlintide Does Not Alter the Responseto Hypoglycemia In Type 1 Diabetes
• Pramlintide did not inhibit the counter-regulatory response to hypoglycemia – Time to counter-regulatory hormone release
and time to glucose recovery unaffected
• No impact on hypoglycemia awareness– Catecholamine responses preserved– Perception of symptoms not diminished
P110
Risk of Hypoglycemia upon Initiation of Pramlintide Therapy in Type 1 Diabetes is Manageable
Plasma Glucose
Glucose Disposal
Food Intake
Self BloodGlucose Monitoring
Insulin Dose
Nausea/Satiety
Start with 10-20% Prandial Insulin Dose Reduction
Educate Patients, DiabetesEducators and Physicians
Initiate TherapyType 1: 30 µg or lower
P111
Pramlintide Benefits are Seen in Patients withType 1 Diabetes Targeting Optimal Glycemic Control
7.2
7.4
7.6
7.8
8
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (Weeks)
MeanHbA1C
(%)
00.51.01.52.02.53.03.54.04.5
Ev
en
t R
ate
Pe
r S
ub
jec
t Y
ea
rWeeks
0-4Weeks
4-26
Severe Hypoglycemia
Ch
an
ge
in
We
igh
t (l
b)
-3
-2
-1
0
1
Weight
0
2
4
6
Ch
an
ge
in
In
su
lin
Us
e (
%)
Insulin Use
Pramlintide (n=243)
Placebo (n=173)
P112
Other Safety ObservationsType 1 Diabetes
• No evidence of:– Serious events that are unusual in the absence
of drug therapy– Cardiac toxicity– Hepatic toxicity– Renal toxicity
• No increase in frequency of clinically significant:– Lipid abnormalities– ECG changes– Changes in vital signs
• Systolic blood pressure• Diastolic blood pressure
– Laboratory abnormalities
P113
Pramlintide is Efficacious and Safein Type 1 Diabetes
• Improves glycemic control • Weight loss• Increased insulin-induced hypoglycemia only
during initiation of therapy– No increase in insulin-induced hypoglycemia after
initiation of therapy
• No other safety issues• Dosage recommendation:
– Initiate at 30 µg 3-4 times/day before meals– Maintenance 30 or 60 µg 3-4 times/day before meals
P114
Guidelines for Initiation of Therapy
• Initial Dose– Type 2: 120 µg – Type 1: 30 µg or lower
• Dose Frequency– Determined by meal pattern– Administered within 15 minutes before a meal
• Insulin Reduction– 10%-20% of preprandial, short-acting insulin dose
P115
Guidelines for Chronic Therapy
• Pramlintide Dose– Type 2: 120 µg – Type 1: 30 or 60 µg
• Insulin Dose– Adjusted according to standard clinical practice– Guided by self blood glucose monitoring
P116
Pramlintide as Adjunctive Therapy to Insulin
Type 2 Diabetes Efficacious Safe Dosage recommendation:
120 µg given 2-3 times/day before meals
Type 1 Diabetes Efficacious Safe Dosage recommendation:
Initiate at 30 µg 3-4 times/day before meals
Maintenance 30 or 60 µg 3-4 times/daybefore meals
P117
Alain Baron, MD
Vice President, Clinical Research,Amylin Pharmaceuticals, Inc.
Professor of Medicine Indiana University, School of Medicine
Risk/Benefit Summary
P118
Risk and Barriers to Current Insulin Therapy
• Hypoglycemia• Inadequate postprandial control
– associated glycemic swings
• Weight gain
• Novel delivery and monitoring devices and insulin analogs are valuable therapeutic advances but still fall short of overcomingthese barriers
WE NEED NEW TOOLS
P119
Risk of Current Insulin Therapy
% H
bA
1c R
edu
ctio
n
• Insulin Dose• Hypoglycemia• Weight Gain
Insulin Alone
P120
Type 2 Diabetes
Pramlintide offers clear benefits outweighing expected,
well recognized andmanageable risks
P121
Type 2 Diabetes —Adjunctive to Insulin Therapy
Risk
Nausea– Mild, infrequent
and transient
Severe Hypoglycemia– No overall
increased risk
Management
– Good clinical care
– Adjustment ofinsulin dose
Pramlintide is safe
P122
Pramlintide Overcomes Barriers and Challengesto Insulin Therapy in Type 2 Diabetes
Barriers
Postprandial hyperglycemia
Weight gain
Hypoglycemia
Hyperinsulinemia
Benefits
– Reduced postprandial glucose excursions
– Weight loss
– No overallincreased risk
– Permits reductionof insulin dose
P123
Type 1 Diabetes
Pramlintide offers clear benefits outweighing expected,
well recognized andmanageable risks
P124
RiskNausea
– Mild-moderate-severe
– Dose-dependentand transient
Management
– Start therapy at30 µg or less
Type 1 Diabetes —Adjunctive to Insulin Therapy
Severe Hypoglycemia– Increased risk
upon initiation– Increased nausea/satiety– Dose-dependent
– Start therapy at30 µg or less
– Adjustment ofinsulin dose
Pramlintide can be used safely
P125
Pramlintide Overcomes Barriers and Challengesto Insulin Therapy in Type 1 Diabetes
Barriers
Hypoglycemia
Weight gain
Postprandial hyperglycemia and glycemic swings
Benefits
– No overallincreased risk
– Possible reduction of risk post-initiation
– Weight loss particularlyin overweight patients
– Reduces postprandial glucose excursions
P126
Is the Reduction in HbA1c Obtainedwith Pramlintide Worthwhile?
• Average reductions in HbA1c of 0.3 – 0.7%vs. insulin alone and 0.5 – 1.0% vs. baselineare worthwhile
• According to DCCT data a 0.5% reductionin HbA1c leads to ~ 30% decrease in riskof retinopathy
P127
Benefit of Pramlintide Therapyin Addition to Insulin
• To further reduce HbA1c and attainglycemic goals
• To control postprandial hyperglycemia
and associated glycemic swings
• Minimize weight gain
P128
Benefits of Pramlintide Therapyin Addition to Insulin
Unique Mode of Action• Limits postprandial glycemic excursions by:
– Suppressing postprandial glucagon secretion(not achievable by exogenous insulin therapy), and
– Modulating the rate of nutrient delivery
• Both effects are complementary and additiveto the actions of insulin to limit postprandialglycemic excursions
P129
Advantages of Addition ofPramlintide to Insulin Therapy
% H
bA
1c R
edu
ctio
n
• Insulin Dose• Hypoglycemia• Weight Gain
Pramlintide + InsulinInsulin Alone
P130
The complementary actions of insulin and pramlintide form a potent binary therapeutic tool
to lower postprandialplasma glucose
P131
Conclusion
Amylin replacement with pramlintide represents anovel and unique therapeutic advance that
fulfills a need for patients withdiabetes treated with insulin