Table of Contents
Joann L. Data, MD, PhD Senior VP, Regulatory Affairs & Quality Assurance Amylin Pharmaceuticals, Inc.
SYMLIN™ (Pramlintide Acetate)
SYMLIN Injection
Amylin’s Presentation
Consultants
Kenneth Polonsky, MD Adolphus Busch Professor of Medicine Chairman, Department of Medicine Washington University School of Medicine
A Century of Diabetes Care
Insulin Therapy Necessary When ?-Cell Fails
Lessons from the DCCT and UKPDS: Continuous Relationship Between Glycemia and Long-Term Complications
Lessons from the DCCT and UKPDS: Sustained Intensification of Therapy is Difficult
Insulin Therapy and Glycemic Control in Young, Insulin-Treated Patients
Lessons from the DCCT and UKPDS: Intervention Works, but is Difficult to Achieve
Our Ability to Achieve Tight Glycemic Control with Insulin Therapy is Limited by:
Barriers to Achieving Glycemic Targets with Insulin in Type 1 Diabetes: Severe Hypoglycemia
Barriers to Achieving Glycemic Targets with Insulin in Type 2 Diabetes: Hypoglycemia
Intensified Insulin Therapy Produces Weight Gain
Impact of Weight Gain on Cardiovascular Risk Factors Type 1 Patients on IIT (n=582), Stratified by Weight Change
Glucose Lowering Efficacy: Importance of Postprandial Hyperglycemia
Daily Log and Sensor Data (24 hrs)
Current Opportunity to Achieve Glycemic Goals
Andrew Young, MD PhD Vice President, Research Amylin Pharmaceuticals, Inc.
Pramlintide Pharmacology
Amylin: a Neuroendocrine Hormone
Amylin Binding/Receptors in Rat Brain
Hormonal Disturbances in Diabetes
Pramlintide: an Analog of Amylin
Three Fluxes Control Blood Glucose
Pramlintide Smoothes Glucose Profiles After Meals in Type 1 Diabetic Humans
Glucoregulatory Actions of Amylin
Pramlintide Suppresses Postprandial Glucagon Secretion
Amylin Inhibits Nutrient-Stimulated, But Not Hypoglycemia-Stimulated Glucagon Secretion in Rats
Pramlintide Does Not Affect Defenses Against Hypoglycemia in Humans
Glucoregulatory Actions of Amylin
Pramlintide Slows Gastric Emptying in Humans with Type 1 Diabetes
Gastric Actions of Amylin Over-ridden by Hypoglycemia in Rats
Amylin-Sensitive Neurons in Area Postrema are Almost All Glucose-Sensitive
Summary: Glucoregulatory Actions of Amylin/Pramlintide
Summary: Rationale for Pramlintide
PPT Slide
Pramlintide Indication
Pramlintide Population
Pramlintide Therapy
Number of Patients Included in Pramlintide Database
Duration of Exposure to Pramlintide All Studies, All Doses
Population Demographics Long-Term, Controlled Studies
Concomitant Medication Use
Pramlintide as Adjunctive Therapy to Insulin in Type 1 and Type 2 Diabetes Results in:
Pramlintide Therapy
Pramlintide Pharmacokinetic Profile Type 1 and Type 2 Diabetes
Addition of Pramlintide to Regular Insulin Therapy Improves Postprandial Glucose Control
Preprandial Addition of Pramlintide Improves Postprandial Glucose Control
Pramlintide Reduces Postprandial Glucose Concentrations in a Dose-Related Manner
Pramlintide Dose-Relationships
PPT Slide
Doses Selected for Phase 3 Studies
Phase 3 Clinical Trials
Study Design Considerations
General Approach to Pramlintide Phase 3 Clinical Studies
Approaches to Insulin Management
Insulin Use in Pramlintide Phase 3 Clinical Studies
Phase 3 Study Design Type 2 and Type 1 Diabetes
Pramlintide Therapy
Type 2 Diabetes Phase 3 Program
Summary of Pramlintide Effects Type 2, Recommended Dose
Pramlintide Phase 3 Studies Type 2 Diabetes HbA1c Effect for Total Population (ITT, 6 months)
Addition of Pramlintide to Insulin Reduces HbA1c in Type 2 Diabetes
Pramlintide Therapy Results in Greater Reduction in HbA1c Than Insulin Alone in Type 2 Diabetes, Recommended Dose (Week 26)
Pramlintide Facilitates Achievement of ADA Targets Type 2 Diabetes, Week 26
Weight Effect Type 2 Diabetes, Week 26
Pramlintide Therapy Offers Unique Metabolic Benefits in Type 2 Diabetes All Patients, Recommended Dose
Pramlintide Therapy
Number of Patients Included in Pramlintide Database
No Increase in Mortality Observed in Type 2 Diabetes Studies
Adverse Event Profile for Type 2 Diabetes Frequent TEAEs (% of Subjects), Overall Incidence > 5%, Excluding Hypoglycemia
Vision/Retinal Disorder Adverse Events
Serious Treatment-Emergent Adverse Events Were Similar (?1% of Subjects)
Severe Hypoglycemia (DCCT Definition) for Type 2 Diabetes Studies
Severe Hypoglycemia Event Rates Type 2 Diabetes All Pramlintide vs. All Placebo
Other Safety Observations Type 2 Diabetes
Pramlintide is Efficacious and Safe in Type 2 Diabetes
Pramlintide Therapy
Type 1 Diabetes Phase 3 Program
Summary of Pramlintide Effects Type 1, Recommended Dose
Pramlintide Phase 3 Studies Type 1 Diabetes HbA1c Effect for Total Population (ITT, 6 months)
Addition of Pramlintide to Insulin Reduces HbA1c in Type 1 Diabetes
Pramlintide Therapy Results in Greater Reduction in HbA1c Than Insulin Alone in Type 1 Diabetes, Recommended Doses (Week 26)
Pramlintide Facilitates Achievement of ADA Targets Type 1 Diabetes, Week 26
Weight Effect Type 1 Diabetes, Week 26
Pramlintide Therapy Offers Unique Metabolic Benefits in Type 1 Diabetes All Patients, Recommended Doses in Type 1
Pramlintide Benefits are Seen in Patients with Type 1 Diabetes Targeting Optimal Glycemic Control
Pramlintide Therapy
Number of Patients Included in Pramlintide Database
No Increase in Mortality Observed in Type 1 Diabetes Studies
Motor Vehicle Accidents/Injuries, All and Hypoglycemia-Related Type 1 Diabetes, Annual Event Rate per Patient-Year
Other Accidents/Injuries (Non-MVA), All and Hypoglycemia-Related Type 1 Diabetes, Annual Event Rate per Patient-Year
Adverse Event Profile for Type 1 Diabetes Frequent TEAEs (% of Subjects), Overall Incidence > 5%, Excluding Hypoglycemia
Most Nausea is Mild to Moderate Pramlintide-Treated Type 1 Patients in Long-Term Controlled Trials
Nausea is Dose Dependent Type 1 Diabetes Long-Term Controlled Studies
PPT Slide
Serious Treatment-Emergent Adverse Events (?1% of Subjects)
Assessment of Severe Hypoglycemia in Long-Term Controlled Trials
Severe Hypoglycemia Annual Event Rate Type 1 Diabetes
Severe Hypoglycemia Annual Event Rate Type 1 Diabetes Excluding Outlier
Severe Hypoglycemia Annual Event Rate over Time Type 1 Diabetes
Severe Hypoglycemia Annual Event Rate by Dose Type 1 Diabetes
Risk for Severe Hypoglycemia Decreases over Time Type 1 Diabetes, All Patients
Risk for Severe Hypoglycemia Decreases over Time Type 1 Diabetes, 30 µg QID
Pramlintide Alone Does Not Cause Hypoglycemia
Pramlintide Does Not Alter the Response to Hypoglycemia In Type 1 Diabetes
Risk of Hypoglycemia upon Initiation of Pramlintide Therapy in Type 1 Diabetes is Manageable
Pramlintide Benefits are Seen in Patients with Type 1 Diabetes Targeting Optimal Glycemic Control
Other Safety Observations Type 1 Diabetes
Pramlintide is Efficacious and Safe in Type 1 Diabetes
Guidelines for Initiation of Therapy
Guidelines for Chronic Therapy
Pramlintide as Adjunctive Therapy to Insulin
PPT Slide
Risk and Barriers to Current Insulin Therapy
Risk of Current Insulin Therapy
PPT Slide
Type 2 Diabetes — Adjunctive to Insulin Therapy
Pramlintide Overcomes Barriers and Challenges to Insulin Therapy in Type 2 Diabetes
PPT Slide
PPT Slide
Pramlintide Overcomes Barriers and Challenges to Insulin Therapy in Type 1 Diabetes
Is the Reduction in HbA1c Obtained with Pramlintide Worthwhile?
Benefit of Pramlintide Therapy in Addition to Insulin
Benefits of Pramlintide Therapy in Addition to Insulin
Advantages of Addition of Pramlintide to Insulin Therapy
PPT Slide
Conclusion
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