Pramlintide Advisory Committee July 26, 2001 Symlin ® Amylin Pharmaceuticals New Drug Application (21-332) Advisory Committee Meeting Bethesda, Maryland.

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

SymlinSymlin®®

Amylin PharmaceuticalsAmylin PharmaceuticalsNew Drug Application (21-332)New Drug Application (21-332)

SymlinSymlin®®

Amylin PharmaceuticalsAmylin PharmaceuticalsNew Drug Application (21-332)New Drug Application (21-332)

Advisory Committee MeetingAdvisory Committee Meeting

Bethesda, MarylandBethesda, Maryland(July 26, 2001)(July 26, 2001)

Advisory Committee MeetingAdvisory Committee Meeting

Bethesda, MarylandBethesda, Maryland(July 26, 2001)(July 26, 2001)

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

EFFICACY - Robert I Misbin, MD• Type 1 diabetes• Type 2 diabetes

SAFETY - Dragos Roman, MD• Hypoglycemia

EFFICACY - Robert I Misbin, MD• Type 1 diabetes• Type 2 diabetes

SAFETY - Dragos Roman, MD• Hypoglycemia

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Type 1 DiabetesType 1 DiabetesType 1 DiabetesType 1 Diabetes

8.2 8.9 8.8 8.9 9.0 8.9 8.9

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Trial 117 - Type 1 DiabetesTrial 117 - Type 1 DiabetesTrial 117 - Type 1 DiabetesTrial 117 - Type 1 Diabetes

Stable metabolic regimen

HbA1c at least 8% at screening

Patients to remain on their usual diet, type of insulin, insulin regimen and exercise regimen

Stable metabolic regimen

HbA1c at least 8% at screening

Patients to remain on their usual diet, type of insulin, insulin regimen and exercise regimen

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

TYPE 1 DIABETESTYPE 1 DIABETESTRIAL 117TRIAL 117

TYPE 1 DIABETESTYPE 1 DIABETESTRIAL 117TRIAL 117

• Mean data at baseline– 38 years old– 16 years of diabetes– BMI 25– HbA1c 9.0%– 50 units insulin/day

• Mean data at baseline– 38 years old– 16 years of diabetes– BMI 25– HbA1c 9.0%– 50 units insulin/day

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

American Diabetes Association American Diabetes Association RecommendationsRecommendations

American Diabetes Association American Diabetes Association RecommendationsRecommendations

• HbA1c <7% Goal of therapy

• HbA1c >8% “additional action suggested”

• HbA1c <7% Goal of therapy

• HbA1c >8% “additional action suggested”

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Trial 117 - Type 1 DiabetesTrial 117 - Type 1 DiabetesTrial 117 - Type 1 DiabetesTrial 117 - Type 1 Diabetes

Stable metabolic regimen

HbA1c at least 8% at screening Patients to remain on their usual diet, type

of insulin, insulin regimen and exercise regimen

Stable metabolic regimen

HbA1c at least 8% at screening Patients to remain on their usual diet, type

of insulin, insulin regimen and exercise regimen

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Type 1 Diabetes Study 117Type 1 Diabetes Study 117Type 1 Diabetes Study 117Type 1 Diabetes Study 117

6.00

6.50

7.00

7.50

8.00

8.50

9.00

9.50

Placebo 90ug bid 60ug tid 90ug tid

HbA

1c BaselineWeek 4Week 26

6.00

6.50

7.00

7.50

8.00

8.50

9.00

9.50

Placebo 90ug bid 60ug tid 90ug tid

HbA

1c BaselineWeek 4Week 26

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Type 1 Diabetes - Trial 117Type 1 Diabetes - Trial 117Type 1 Diabetes - Trial 117Type 1 Diabetes - Trial 117

• “Early Glycemic Responder” Subgroup

• Reduction in HbA1c at least 0.5% units at 4 weeks

• Show data at 4 and 26 weeks

• “Early Glycemic Responder” Subgroup

• Reduction in HbA1c at least 0.5% units at 4 weeks

• Show data at 4 and 26 weeks

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Early Glycemic Responders Early Glycemic Responders Study117Study117

Early Glycemic Responders Early Glycemic Responders Study117Study117

Placebo 60ugTID

90ugBID

90ugTID

% of ITT 25% 44% 41% 44%

HbA1creduction: 4 Weeks: -0.83 -0.86 -0.79 -0.93

26 weeks: -0.48 -0.55 -0.42 -0.49

Placebo 60ugTID

90ugBID

90ugTID

% of ITT 25% 44% 41% 44%

HbA1creduction: 4 Weeks: -0.83 -0.86 -0.79 -0.93

26 weeks: -0.48 -0.55 -0.42 -0.49

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Early Glycemic Responders 117Early Glycemic Responders 117Early Glycemic Responders 117Early Glycemic Responders 117

Placebo 60ugTID

90ugBID

90ugTID

% of ITT 25% 44% 41% 44%

At 26 Weeks:

HbA1c -0.48 -0.55 -0.42 -0.49

Insulin, % +1.9% -4.1% -2.0% +0.6%

Weight, kg +1.0 -2.0 -0.4 -1.6

Placebo 60ugTID

90ugBID

90ugTID

% of ITT 25% 44% 41% 44%

At 26 Weeks:

HbA1c -0.48 -0.55 -0.42 -0.49

Insulin, % +1.9% -4.1% -2.0% +0.6%

Weight, kg +1.0 -2.0 -0.4 -1.6

SevereHypoglycemia**events per patient year

0.2 1.0 1.6 1.7

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Early Glycemic Responders 117Early Glycemic Responders 117Early Glycemic Responders 117Early Glycemic Responders 117

Placebo 60ugTID

90ugBID

90ugTID

% of ITT 25% 44% 41% 44%

Baseline HbA1c 9.78 9.27 9.25 9.14

At 4 Weeks:

HbA1c -0.83 -0.86 -0.79 -0.93

Severe * Hypoglycemia

0.4 1.5 4.9 3.6

*events per patient year

Placebo 60ugTID

90ugBID

90ugTID

% of ITT 25% 44% 41% 44%

Baseline HbA1c 9.78 9.27 9.25 9.14

At 4 Weeks:

HbA1c -0.83 -0.86 -0.79 -0.93

Severe * Hypoglycemia

0.4 1.5 4.9 3.6

*events per patient year

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Pramlintide Treatment of Pramlintide Treatment of Type 1 DiabetesType 1 Diabetes

Pramlintide Treatment of Pramlintide Treatment of Type 1 DiabetesType 1 Diabetes

• 3-4 injections per day in addition to insulin

• More severe hypoglycemia than reducing

HbA1c with insulin alone

• Weight loss relative to insulin alone

• 3-4 injections per day in addition to insulin

• More severe hypoglycemia than reducing

HbA1c with insulin alone

• Weight loss relative to insulin alone

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Type 2 DiabetesType 2 DiabetesType 2 DiabetesType 2 Diabetes

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

TYPE 2 DIABETESTYPE 2 DIABETESTRIAL 123TRIAL 123

TYPE 2 DIABETESTYPE 2 DIABETESTRIAL 123TRIAL 123

• Mean data at baseline– 58 years old– 13 years of diabetes– BMI 30.6 – HbA1c 9.4%– 56 units insulin/day

• Mean data at baseline– 58 years old– 13 years of diabetes– BMI 30.6 – HbA1c 9.4%– 56 units insulin/day

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Trial 123 - Type 2 DiabetesTrial 123 - Type 2 DiabetesTrial 123 - Type 2 DiabetesTrial 123 - Type 2 Diabetes

HbA1c at least 8% at screening

Patients to remain on their usual diet, insulin regimen, and exercise regimen

“changes in insulin doses were not encouraged in order to limit the impact of alterations in insulin dosing on glycemic control.”

HbA1c at least 8% at screening

Patients to remain on their usual diet, insulin regimen, and exercise regimen

“changes in insulin doses were not encouraged in order to limit the impact of alterations in insulin dosing on glycemic control.”

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Type 2 Diabetes Study 123Type 2 Diabetes Study 123Type 2 Diabetes Study 123Type 2 Diabetes Study 123

6.00

6.50

7.00

7.50

8.00

8.50

9.00

9.50

Placebo 90ug bid 120ug bid 90ug tid

Hb

A1c Baseline

Week 13Week 26

6.00

6.50

7.00

7.50

8.00

8.50

9.00

9.50

Placebo 90ug bid 120ug bid 90ug tid

Hb

A1c Baseline

Week 13Week 26

ITT population

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Type 2 Diabetes MetforminType 2 Diabetes MetforminType 2 Diabetes MetforminType 2 Diabetes Metformin

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

HbA

1c BaselineWeek 24

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

HbA

1c BaselineWeek 24

Annals of Internal Medicine 1999; 131:185

-0.9

Insulin +Metformin

Insulin + Placebo

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Insulin +Placebo

Insulin +Metformin

Baseline HbA1c 9.1 9.0

Change -1.6 -2.5

Difference -0.9

Baseline Insulin dose, U/d 97 96

Change +23 -5

Difference -27

Baseline Weight, kg 106.6 103.9

Change +3.2 +0.5

Difference -2.7

Insulin +Placebo

Insulin +Metformin

Baseline HbA1c 9.1 9.0

Change -1.6 -2.5

Difference -0.9

Baseline Insulin dose, U/d 97 96

Change +23 -5

Difference -27

Baseline Weight, kg 106.6 103.9

Change +3.2 +0.5

Difference -2.7

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

Type 2 Diabetes Study 123Type 2 Diabetes Study 123Type 2 Diabetes Study 123Type 2 Diabetes Study 123

6.00

6.50

7.00

7.50

8.00

8.50

9.00

9.50

Placebo 90ug bid 120ug bid 90ug tid

Hb

A1c Baseline

Week 13Week 26

6.00

6.50

7.00

7.50

8.00

8.50

9.00

9.50

Placebo 90ug bid 120ug bid 90ug tid

Hb

A1c Baseline

Week 13Week 26

ITT population

Pramlintide Advisory Committee Pramlintide Advisory Committee July 26, 2001July 26, 2001

SAFETY REVIEWSAFETY REVIEWSAFETY REVIEWSAFETY REVIEW

• Dr Dragos Roman• Dr Dragos Roman