# Presentation: 301998

## Joann L. Data, MD, PhDSenior VP, Regulatory Affairs & Quality AssuranceAmylin Pharmaceuticals, Inc.

**Overview**

## SYMLINTM(Pramlintide Acetate)

**Amylin Pharmaceuticals, Inc.**

## SYMLIN Injection

**Indication:**
**	****Adjunctive therapy to insulin,****to improve glycemic and metabolic control****in people with type 1 or type 2 diabetes**
**Administration:**
**	****Injected subcutaneously approximately****15 minutes prior to a meal**
**Presentations:**
**	****Vials and cartridges**

## Amylin’s Presentation

**Unmet Medical Need****	****	****Kenneth Polonsky, MD****	****	****	****	****	****Chairman, Department of Medicine**
**	****	****	****	****	****	****Washington University**
**Pramlintide Pharmacology****	****Andrew Young, MD, PhD****	****	****	****	****	****	****VP Research****	****	****	****	****	****Amylin Pharmaceuticals**
**Clinical Program****	****	****Orville Kolterman, MD****	****	****	****	****	****Senior**** ****VP**** ****Clinical Affairs****	****	****	****	****	****	****Amylin Pharmaceuticals**
**Risk/Benefit Summary ****	****Alain Baron, MD****	****	****	****	****	****	****	****VP**** ****Clinical Research**** ****	****	****	****	****	****	****Amylin Pharmaceuticals**

## Consultants

**Hugh E. Black, DVM, PhD****Toxicology Consultant**
**	****Hugh E. Black and Associates, Inc. **
**Wayne Colburn, PhD**
**	****Pharmacokinetics Consultant****MDS ****Pharma Services**
**Richard Dickey, MD**
**	****Clinical Consultant**
**	****Private Practice,****Hickory, NC****	**

**Kerry Hafner, PhD**
**	****Statistical Consultant**
**	****PRA International**
**Kenneth Polonsky, MD****Clinical Consultant****Washington University**

## Kenneth Polonsky, MDAdolphus Busch Professor of MedicineChairman, Department of MedicineWashington University School of Medicine 

**Unmet Medical Need**

## A Century of Diabetes Care

**Type 1**

**Insulin therapy**

**A Century of Diabetes Care**

**Pump therapy**

**Human insulin**

**Insulin analogs**

**NPH insulin**

**Oral Agents**

**Type 2**

**Insulin therapy**

## Insulin Therapy NecessaryWhen -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**

## Lessons from the DCCT and UKPDS:Continuous Relationship Between Glycemiaand Long-Term Complications 

***Lancet  *****1998;352:837-853**

**DCCT (Type 1)**

**Retinopathy**

**16**

**12**

**8**

**4**

**0**

**5**

**6**

**7**

**8**

**9**

**10**

**11**

**12**

**HbA****1c**** (%)**

**Rate/100 Patient Years**

**UKPDS (Type 2)**

**HbA****1c**** (%)**

**Incidence/100 Patient Years**

**8**

**6**

**4**

**2**

**0**

**5**

**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**

## Lessons from the DCCT and UKPDS:Sustained Intensification of Therapy is Difficult

**8.8**

**8.1**

**7.2**

**7.7**

**4**

**6**

**8**

**10**

**HbA****1c**** (%)**

**0**

**6**

**7**

**8**

**0**

**2**

**4**

**6**

**8**

**10   yrs**

**HbA****1c**** (%)**

**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.**

## 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**

**HbA****1c**

**0**

**4**

**10   yrs**

**2%**

**6%**

**8%**

**10%**

**4%**

**0%**

**Short Acting**
**Short and Long Acting**
**Long Acting**

**3 or more**
**2**
**1**

## 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 limit****of normal range**

**ADA:****intensification advised**

**7%**

**8%**

**9%**

**6%**

**HbA****1c**

**10%**

**8.8%**

**El-Kebbi IM, *****Arch Intern Med***** 161: 1295-301 2001**

**9.1%**

**Klein et al, *****Diabetes Care***** 19: 744-750 1996**

**9.6%**

**Type 2 Patients, Hiss et al, ADA 2001**

**9.8%**

**Type 1 Patients, Hiss et al, ADA 2001**

## Our Ability to Achieve Tight Glycemic Control with Insulin Therapy is Limited by:

**Hypoglycemia **
**Weight Gain **
**Postprandial hyperglycemia**

## Barriers to Achieving Glycemic Targets with Insulin in Type 1 Diabetes: Severe Hypoglycemia

**DCCT Research Group,***** Diabetes***** 1997;46:271-286 **

**HbA****1c**** (%) During Study**

**100**

**80**

**60**

**40**

**20**

**0**

**5**

**6**

**7**

**8**

**9**

**10**

**11**

**12**

**13**

**14**

**Rate/100 Patient Years**

**Conventional**

**Intensified**

**Intensified regimens result in ****3- to 4-fold higher severe hypoglycemia event rates****than conventional regimens**

## 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**

**Major Episodes Incidence (%)**

**Intensification with Insulin**

***Pioglitazone NDA, 1998******Kelley et al, Diabetes Care 21: 2056-61, 1998***

**5%**
**8%**
**15%**

**22%**
**29%**

## Intensified Insulin TherapyProduces Weight Gain

**DCCT (Type 1)**

**UKPDS (Type 2)**

**Intensified Insulin Therapy****Produces Weight Gain**

*** ******Diabetes Care *****1988;11:567-573**
***JAMA***** 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**

**Mean change in weight (kg)**

**0**

**3**

**6**

**9**

**12**

**15**

**7.5**

**5.0**

**2.5**

**0.0**

**Intensified**

**Conventional**

**Change in weight (kg)**

**Years from Randomization**

## Impact of Weight Gainon Cardiovascular Risk FactorsType 1 Patients on IIT (n=582), Stratified by Weight Change

**1****st**
**Quartile**

**2****nd**
**Quartile**

**3****rd**
**Quartile**

**4****th**
**Quartile**

**120**
**118**
**116**
**114**
**112**
**110**

**A**

**Systolic BP**

**mm Hg**

**1****st**
**Quartile**

**2****nd**
**Quartile**

**3****rd**
**Quartile**

**4****th**
**Quartile**

**80**
**78**
**76**
**74**
**72**
**70**

**B**

**Diastolic BP**

**mm Hg**

**1****st**
**Quartile**

**2****nd**
**Quartile**

**3****rd**
**Quartile**

**4****th**
**Quartile**

**90**
**85**
**80**
**75**
**70**
**65**

**C**

**Triglycerides**

**mg/dL**

**1****st**
**Quartile**

**2****nd**
**Quartile**

**3****rd**
**Quartile**

**4****th**
**Quartile**

**D**

**Total Cholesterol**

**mg/dL**

**195**
**190**
**185**
**180**
**175**
**170**

**Purnell J,***** JAMA***** 1998;280:140-146**

## Glucose Lowering Efficacy:Importance of Postprandial Hyperglycemia 

**Polonsky 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**

**Glucose  (mg/dL)**

**DIABETIC**

**CONTROL**

## Daily Log and Sensor Data (24 hrs)

**Target Range**

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**350**

**400**

**Glucose (mg/dL)**

**Sensor Measurement**

**Insulin Bolus**

**Fingerstick Measurement**

**Daily Log and Sensor Data (24 hrs)**

**8AM     12 Noon              7PM        Midnight**

**Age: 44 years**

**HbA****1c ****7.1%**

**Type 1 Patient**

## Current Opportunity toAchieve Glycemic Goals

**Control Postprandial Glucose**
**Without Weight Gain**
**Without Increasing Hypoglycemia**

## Andrew Young, MD PhDVice President, ResearchAmylin Pharmaceuticals, Inc.

**Pramlintide Pharmacology**

## 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**

## 37-amino acid peptide
Located almost entirely in -cells
Co-secreted with insulin during meals 
Receptor characterized in CNS

**Located almost entirely in ********-cells**
**Co-secreted with insulin during meals **
**Receptor characterized in CNS**

**Healthy subjects**
**n = 6**

**Plasma insulin (pM)**

**Plasma amylin (pM)**

**7 am**

**Midnight**

**5 pm**

**12 noon**

**Time**

**Amylin**

**Insulin**

**600**

**400**

**200**

**0**

**Adapted from Koda JE, et al.*****  Diabetes 1995.***

**Amylin: a Neuroendocrine Hormone**

## Amylin Binding/Receptors in Rat Brain

## Hormonal Disturbances in Diabetes

**Insulin Deficiency**
**Amylin Deficiency **
**Glucagon Excess**

**Unger et al., *****J Clin. Invest*****. 1970**
**Dobbs et al., *****Science***** 1975.**

**Fineman et al.,  *****Diabetologia***** 1996****Data on file**

**Insulin-using**
**Type 2 **

**Time after liquid meal (min)**

**-30**

**0**

**30**

**60**

**90**

**120**

**150**

**180**

**Non-diabetic**

**Type 1 **

**Plasma****amylin****(pM)**

## 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**

## Three Fluxes Control Blood Glucose

**Three Fluxes Control Blood Glucose**

**Glucagon**

**Amylin**

**Insulin**

**Meal**

**Glucose**

## 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**

**Change in glucose (mg/dL)**

**Placebo**

**10 ****μg**

**30 ****μg**

**60 ****μg**

**100 ****μg**

**300 ****μg**

## Glucoregulatory Actions of Amylin

*****

*****

*** ****In man**

**Glucagon**
**Secretion**

**Amylin**

**Glucose**

**Insulin**

**Satiety**

**Gastric Emptying**

**Digestion**

## Pramlintide Suppresses Postprandial Glucagon Secretion

**Pramlintide Suppresses ****Postprandial Glucagon Secretion**

** ****Pram 30 ********g + Ins (N=14)**

**                           ****P<0.05, incremental AUC**

** ****Placebo + Ins (N=20)**

**Mean change  in plasma glucagon (pg/mL)**

**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**

**Mean change  in plasma glucagon (pg/mL)**

** ****Injection**

**Type 1 diabetes****, SC injection**

**Type 2 diabetes****, IV infusion**

## Amylin Inhibits Nutrient-Stimulated,But Not Hypoglycemia-StimulatedGlucagon Secretion in Rats

**Amylin Inhibits Nutrient-Stimulated,****But Not Hypoglycemia-Stimulated****Glucagon Secretion in Rats**

**Glucose    6mM (clamped)       2mM (hypo)**

**-60**

**60**

**180**

**240**

**0**

**120**

**0**

**100**

**200**

**300**

**Saline**

**Amylin**

**500**

**1000**

**L-Arginine**

**Minutes**

**Glucagon**
**(pM)**

**Silvestre et al., Am. J. *****Physiol***** 2001.**

## 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 response****to glucagon intervention**

**Study AP93-04, AP93-08**

## Glucoregulatory Actions of Amylin

**Glucoregulatory Actions of Amylin**

*** ****In man**

**Amylin**

**Glucose**

**Insulin**

**Digestion**

**Glucagon**
**Secretion**

**Satiety**

**Gastric Emptying**

*****

*****

## Pramlintide Slows Gastric Emptyingin Humans with Type 1 Diabetes

**Gastric****half-emptying time****(hours)**

**** p < 0.004 vs. placebo***

**0**

**1**

**2**

**3**

**4**

**90 μg**

**60 μg**

**30 μg**

**Placebo**

*****

*****

*****

***Single SC doses (N = 11, crossover);***
***Tc-99m labelled pancake;***
***solid component measured***

**~1 hour delay**

**Pramlintide Slows Gastric Emptying****in Humans with Type 1 Diabetes**

**Kong et al.***** Diabetologia***** 1998.**

## 

Enables oral rescue from hypoglycemia

**Enables oral rescue from hypoglycemia**

**Gastric Actions of Amylin****Over-ridden by Hypoglycemia in Rats**

## Amylin-Sensitive Neurons in Area Postrema are Almost All Glucose-Sensitive

**0**

**60**

**120**

**180**

**Minutes**

**0**

**2**

**4**

**12**

**Spikes**
**per sec**

**2**

**4**

**6**

**Glucose mM**

**Amylin 10nM**

## Summary: Glucoregulatory Actionsof Amylin/Pramlintide

**Inhibits nutrient stimulated glucagon secretion**
**Regulates nutrient uptake from the meal**** **
**Glucose-lowering actions over-ridden****during hypoglycemia**

## Summary:  Rationale for Pramlintide

**Pramlintide replaces absent amylin**** **
**Pramlintide restores control of glucose influx  ****Complements insulin control of glucose efflux  **

## Orville G. Kolterman, MDSenior Vice President, Clinical Affairs,Amylin Pharmaceuticals, Inc. Adjunct Professor of Medicine University of California, San Diego 

**Clinical Program**

## Pramlintide Indication

**Adjunctive therapy to insulin,**
**to improve glycemic and metabolic control**
** ****in people with type 1 or type 2 diabetes**

## Pramlintide Population 

**ß-cell****function**

**Disease Progression**

**Diet****Exercise**

***PLUS***
**Oral agent**

***Normal***

***Absent***

**Type 2**

***PLUS***
**Combination**
**Oral agents**

**Type 1**

**Pramlintide Population **

***PLUS***
**Insulin**

## Pramlintide Therapy

**Program Overview**
**Pharmacodynamic Review**
**Type 2 Diabetes**
**Efficacy**
**Safety**
**Type 1 Diabetes**
**Efficacy**
**Safety**

## Number of Patients Includedin Pramlintide Database

**TOTAL PATIENTS**

**Number of Patients Included****in Pramlintide Database**

**Clin Pharm / Others**

**Total Patient-Yr Exposure**

**Type 2 Diabetes**

***-Long-term, controlled***

**Type 1 Diabetes**

***-Long-term, controlled***

## Duration of Exposure to Pramlintide  All Studies, All Doses

**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**

## Population DemographicsLong-Term, Controlled Studies

**Age (mean years)**

**Duration of diabetes (mean yrs)**

**HbA****1c**** (mean %)**

**BMI (mean kg/m****2****)**

**Type 1****Studies**

**Type 2****Studies**

**40**

**17**

**8.9**

**26**

**57**

**12**

**9.2**

**32**

## Concomitant Medication Use

| 
% 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**

## Pramlintide as Adjunctive Therapy to Insulin in Type 1 and Type 2 Diabetes Results in:

**Further improvement in glycemic control**
**Postprandial glucose**
**HbA****1c**
**No increase in insulin use**
**Weight loss**

## Pramlintide Therapy

**Program Overview**
**Pharmacodynamic Review**
**Type 2 Diabetes**
**Efficacy**
**Safety**
**Type 1 Diabetes**
**Efficacy**
**Safety**

## Pramlintide Pharmacokinetic ProfileType 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**

**Plasma Pramlintide Concentration (pmol/L)**

**1 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**

**Plasma Pramlintide Concentration (pmol/L)**

**Type 2 Diabetes**

**Hours from Initial Dosing**

**1 x 60 μg Pramlintide**

**1 x 90 μg Pramlintide**

**1 x 120 μg Pramlintide**

## Addition of Pramlintide to Regular Insulin TherapyImproves Postprandial Glucose Control

**Plasma Pramlintide (pM)**

**N=15**

**0**

**30**

**60**

**90**

**120**

**150**

**180**

**0**

**25**

**50**

**Time (min)**

**Kolterman et al., *****Diabetologia***** 1996.**

**Plasma Glucose**

**Plasma Glucose (mg/dL)**

**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 Therapy****Improves Postprandial Glucose Control**

**Mean (SE)**

**Type 1 Diabetes**

## Preprandial Addition of Pramlintide Improves Postprandial Glucose Control

**Time (minutes)**

**-30**

**0**

**30**

**60**

**120**

**270**

**360**

**180**

**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**

**Lunch**

**Breakfast**

**p=0.001 post-breakfast****p=0.02 post-lunch**

**137-107**

**Preprandial Addition of Pramlintide Improves Postprandial Glucose Control**

**Mean (SE)**

**Type 1 Diabetes, 28 Day Study**

## 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**

**Change in Glucose (mg/dL)**

**Placebo**

**10 ****μg**

**30 ****μg**

**60 ****μg**

**100 ****μg**

**300 ****μg**

**Type 1 Diabetes**

**AP93-08, 137-104, 137-105**

## Pramlintide Dose-Relationships

**Pramlintide Dose-Relationships**

** **

** **

** **

** **

** **

** **

** **

** **

** **

** **

** **

** **

**-4000**

** **

**-2000**

** **

**0**

** **

**2000**

** **

**4000**

** **

**6000**

** **

**8000**

** **

**10000**

** **

**12000**

** **

**14000**

** **

**Mean Glucose Incremental AUC **

** **

**(mg•min/dL, 0-180 min)**

** **

** **

** **

** **

**AP93-08, 137-104, 137-105**

**Type 1 Diabetes**

**Line ****= Mean Glucose AUC**

**Dose Response Test: P = 0.012**

## Pramlintide Dose-Relationships

**Mean Change in % HbA1c****From Baseline**

**Line ****= Mean HbA****1c**

**Type 2 Diabetes, Week 13**

**-1.0**

**-0.8**

**-0.6**

**-0.7**

**-0.9**

**-1.1**

## Doses Selected for Phase 3 Studies

**Type 2 diabetes range: 30 to 150 μg **
**Type 1 diabetes range: 30 to 90 μg **

## Phase 3 Clinical Trials

**Demonstration of efficacy**
**Assessment of safety **
**Guidance for clinical use**

## Study Design Considerations

**No precedent for efficacy studies****in insulin-treated subjects**
**DCCT established HbA****1c**** as surrogate****endpoint for glycemic control**
**On-going debate regarding “threshold effect” **
**Ancillary metabolic effects (weight, insulin use, ****lipid profile) not fully appreciated**

## General Approach to PramlintidePhase 3 Clinical Studies

**All subjects were treated with insulin**
**All studies employed an “add-on” design**
**Pramlintide or placebo was added****to existing therapies**
**Oral hypoglycemic agents were****to be unchanged **
**Sulfonylurea**
**Metformin**

## 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**

## Insulin Use in PramlintidePhase 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**

## Phase 3 Study DesignType 2 and Type 1 Diabetes

**Multicenter, randomized, placebo-controlled**
**Primary endpoint**
**HbA****1c****, week 26 or 52 **
**Secondary endpoints**
**Weight**
**Insulin use**
**Safety parameters**

## Pramlintide Therapy

**Program Overview**
**Pharmacodynamic Review**
**Type 2 Diabetes**
**Efficacy**
**Safety**
**Type 1 Diabetes**
**Efficacy**
**Safety**

## Type 2 Diabetes Phase 3 Program

## Summary of Pramlintide EffectsType 2, Recommended Dose

**HbA****1c**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**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**

**Mean (SE) Change in HbA****1c**

**0**

**1**

**2**

**3**

**4**

**5**

**0-4**

**4-26**

**26-52**

**Time (Weeks)**

**Event **

**Rate/**

**Subject**

**Year**

**Time (Weeks)**

**Overall Nausea**

**Severe Hypoglycemia**

**Placebo + Insulin (n=207) ***

**Pramlintide + Insulin (n=222) ***

******** *****Evaluable Population**

## Pramlintide Phase 3 Studies Type 2 DiabetesHbA1c Effect for Total Population (ITT, 6 months)

**Pramlintide Phase 3 Studies Type 2 Diabetes****HbA****1c**** Effect for Total Population (ITT, 6 months)**

**Mean (SE)********HbA****1c**** (%)**

**0**

**-0.4**

**-0.3**

**-0.2**

**-0.1**

**-0.5**

**-0.6**

**-0.7**

**-0.8**

**Dosage Recommendation:  120 ****μg ****given 2-3 times/day**

## Addition of Pramlintide to Insulin ReducesHbA1c in Type 2 Diabetes

**Stable Insulin**

**ITT**

- 137-122

**Placebo + Insulin  ****	****n=161**

**Pramlintide 120 BID + Insulin ****	****n=166**

**Placebo + Insulin  ****	****n=55**

**Pramlintide 120 BID + Insulin ****	****n=70**

## Pramlintide Therapy Results in Greater Reduction in HbA1c Than Insulin Alone in Type 2 Diabetes, Recommended Dose (Week 26) 

**Cumulative Percent ******

**Cumulative Percent ******

**100**

**90**

**80**

**70**

**60**

**50**

**40**

**30**

**20**

**10**

**0**

**-2**

**-1**

**0**

**1**

**2**

**-1.5**

**0.5**

**0.5**

**1.5**

## Pramlintide FacilitatesAchievement 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**

## Weight EffectType 2 Diabetes, Week 26

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

**1**

**2**

**3**

**Mean (SE) ********  Weight (lb)**

## Pramlintide Therapy Offers Unique Metabolic Benefits in Type 2 Diabetes All Patients, Recommended Dose

**Change in % HbA****1c**

**Week 4**

**Week 13**

**Week 26**

**Change in Weight (lb)**

**Week 4**

**Week 13**

**Week 26**

**Change in Insulin Use (%)**

**Week 4**

**Week 13**

**Week 26**

**Pramlintide Therapy Offers Unique Metabolic Benefits in Type 2 Diabetes ****All Patients, Recommended Dose**

**Placebo + Insulin (N=284)**

**Baseline:**** 9.3  9.1**

## Pramlintide Therapy

**Program Overview**
**Pharmacodynamic Review**
**Type 2 Diabetes**
**Efficacy**
**Safety**
**Type 1 Diabetes**
**Efficacy**
**Safety**

## Number of Patients Includedin Pramlintide Database

**TOTAL PATIENTS**

**Number of Patients Included****in Pramlintide Database**

**Clin Pharm / Others**

**Total Patient-Yr Exposure**

**TOTAL PATIENTS**

**Type 2 Diabetes**

***-Long-term, controlled***

**Type 1 Diabetes**

***-Long-term, controlled***

## No Increase in Mortality Observedin Type 2 Diabetes Studies

**Placebo**

**Cardiac****	**

**Sudden Death****	**

**Total**

**4 (0.75%)**

**1 (0.19%)**

**5 (0.94%)**

**(n = 532)**

**No Increase in Mortality Observed****in Type 2 Diabetes Studies**

**10 deaths occurred among 2195 unique subjects****in type 2 diabetes studies**
**None classified as drug related**

**Pramlintide**

**	**

**Cardiac****	**

**Total**

**5 (0.30%)**

**5 (0.30%)**

**(n = 1663)**

## Adverse Event Profile for Type 2 DiabetesFrequent TEAEs (% of Subjects), Overall Incidence > 5%,Excluding Hypoglycemia

| % of Subjects | Placebo
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 |

## Vision/Retinal Disorder Adverse Events

**One study (137-111) had an apparent increase****in 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 **

## Serious Treatment-Emergent  Adverse Events Were Similar (1% of Subjects)

**Pramlintide **

**Type 2**

**Serious Treatment-Emergent  Adverse Events Were Similar (********1% of Subjects)**

***Body System:***

**Events different between pramlintide and placebo **

## Severe Hypoglycemia (DCCT Definition)for Type 2 Diabetes Studies

**Severe Hypoglycemia (DCCT Definition)****for Type 2 Diabetes Studies**

**Number and incidence****of patients with at least****1 hypoglycemia episode **

**Patient exposure (years)**

** **

**Number of hypoglycemic****events**

**Placebo **

**17 (6%)**

**188**

**0.21**

**40**

**Pramlintide**

**76 (9%)**

**587**

**0.24**

**139**

**Number of hypoglycemic****events per one year of****patient time**

**137-122, 137-123 Combined (ITT)**

## Severe Hypoglycemia Event RatesType 2 Diabetes All Pramlintide vs. All Placebo

**0.2**

**0.5**

**0.2**

**0.3**

**0.3**

**0.1**

**0**

**1**

**2**

**3**

**4**

**5**

**Mean (SE)**
**Event**
**Rate Per**
**Subject**
**Year**

**Pram + Ins**

**Pbo + Ins**

**n=284**

**n=871**

**n=820**

**n=267**

**Pram + Ins**

**Pbo + Ins**

**Pram + Ins**

**Pbo + Ins**

**n=576**

**Weeks 0-4**

**Weeks 4-26 **

**Weeks 26-52 **

**n=175**

## Other Safety ObservationsType 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**

## Pramlintide is Efficacious and Safein 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**

## Pramlintide Therapy

**Program Overview**
**Pharmacodynamic Review**
**Type 2 Diabetes**
**Efficacy**
**Safety**
**Type 1 Diabetes**
**Efficacy**
**Safety**

## Type 1 Diabetes Phase 3 Program

**Endpoint**** Assessments (Week)**

**4**

**0**

**13**

**39**

**26**

**20**

**52**

**Randomization**

**Placebo ****Lead-In**

**137-112**

**PBO, Pram 30 QID**

**Pram 30 QID / 60 QID**

***Re-randomization***

**N = 480**

**137-121**

**PBO, Pram 60 TID, 60 QID or 90 TID **

**N = 651**

**137-117**

**PBO, Pram 60 TID, 90 BID or 90 TID **

**N = 586**

**Metabolic****Stability**

## Summary of Pramlintide EffectsType 1, Recommended Dose

**-0.7**

**-0.6**

**-0.5**

**-0.4**

**-0.3**

**-0.2**

**-0.1**

**0**

**0**

**13**

**26**

**39**

**52**

**Mean (SE) Change in HbA1c**

**HbA****1c**

**Overall Nausea**

**Severe Hypoglycemia**

**0**

**1**

**2**

**3**

**4**

**5**

**0-4**

**4-26**

**26-52**

**Time (Weeks)**

**Event**

**Rate/**

**Subject**

**Year**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0-4**

**4-26**

**26-52**

**Time (Weeks)**

**Incidence**

**(%)**

**Placebo + Insulin (n=393)***

**Pramlintide + Insulin (496)***

**Time (Weeks)**

******** *****Evaluable Population**

## Pramlintide Phase 3 Studies Type 1 DiabetesHbA1c Effect for Total Population (ITT, 6 months)

- 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**

**-0.5**

**Mean (SE)********HbA****1c**** (%)**

**-0.6**

**+0.1**

**Pramlintide Phase 3 Studies Type 1 Diabetes****HbA****1c**** 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**

## Addition of Pramlintide to Insulin ReducesHbA1c in Type 1 Diabetes

**Stable Insulin**

**ITT**

**Placebo + Insulin**

**Pram 60 TID + Insulin**

**Pram 60 QID + Insulin**

- 137-121

**Mean (SE)**

## Pramlintide Therapy Results in Greater Reduction in HbA1c Than Insulin Alone in Type 1 Diabetes, Recommended Doses (Week 26)

**Change in HbA**

**1C**

** ****(%) From Baseline**

**Placebo**

**Pramlintide 30/60 QID**

**Pramlintide 60 TID**

**Pramlintide 60 QID**

**Pramlintide Therapy Results in Greater Reduction in HbA****1c**** Than Insulin Alone in Type 1 Diabetes, Recommended Doses (Week 26)**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**Cumulative Percent ******

**Cumulative Percent ******

**100**

**90**

**80**

**70**

**60**

**50**

**40**

**30**

**20**

**10**

**0**

**-2**

**-1**

**0**

**1**

**2**

**-1.5**

**0.5**

**0.5**

**1.5**

## Pramlintide FacilitatesAchievement 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% |

## Weight Effect Type 1 Diabetes, Week 26

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

**1**

**2**

**3**

**Mean (SE) ******** Weight (lb)**

**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

## Pramlintide Therapy Offers Unique Metabolic Benefits in Type 1 Diabetes All Patients, Recommended Doses in Type 1

**Change in % HbA****1c**

**Week 4**

**Week 13**

**Week 26**

**Change in Weight (lb)**

**-3**

**-2**

**-1**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**Week 4**

**Week 13**

**Week 26**

**Change in Insulin Use (%)**

**-3.0**

**-2.5**

**-2.0**

**-1.5**

**-1.0**

**-0.5**

**0**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**Week 4**

**Week 13**

**Week 26**

**Placebo + Insulin (N=538)**

**Baseline:**** 9.0  8.9**

## Pramlintide Benefits are Seen in Patients with Type 1 Diabetes Targeting Optimal Glycemic Control

**Change in Insulin Use (%)**

**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**

**Change in Weight (lb)**

**Weight**

**Mean****HbA****1C****(%)**

## Pramlintide Therapy

**Program Overview**
**Pharmacodynamic Review**
**Type 2 Diabetes**
**Efficacy**
**Safety**
**Type 1 Diabetes**
**Efficacy**
**Safety**

## Number of Patients Includedin Pramlintide Database

**TOTAL PATIENTS**

**Number of Patients Included****in Pramlintide Database**

**Clin Pharm / Others**

**Total Patient-Yr Exposure**

**TOTAL PATIENTS**

**Type 2 Diabetes**

***-Long-term, controlled***

**Type 1 Diabetes**

***-Long-term, controlled***

## No Increase in Mortality Observedin Type 1 Diabetes Studies

**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 Observed****in Type 1 Diabetes Studies**

**7 deaths occurred among 3477 unique subjects**
**1 classified as “possibly drug related”**

**Multi-Organ Failure**

**1 (0.04%)**

## Motor Vehicle Accidents/Injuries,All and Hypoglycemia-Related Type 1 Diabetes, Annual Event Rate per Patient-Year

**0.01**

**0.02**

**0.03**

**0.04**

**0.05**

**0.06**

**0.07**

**0.08**

**0.09**

**Annual Event Rate per Patient-Year (±95% CI)**

**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**

**0.00**

**Pramlintide**

**(28 of 2573 pts)**

**All**

**Placebo**

**(7 of 904 pts)**

**Pramlintide**

**(17 of 2573 pts)**

**p=0.13**

**p=0.56**

## Other Accidents/Injuries (Non-MVA),All and Hypoglycemia-Related Type 1 Diabetes, Annual Event Rate per Patient-Year

**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**

**All****Accidents/Injuries**

**Annual Event Rate per Patient-Year (±95% CI)**

**Placebo**

**Pramlintide**

**Placebo**

**Pramlintide**

**p=1.00**

**p=0.59**

## Adverse Event Profile for Type 1 DiabetesFrequent TEAEs (% of Subjects), Overall Incidence > 5%,Excluding Hypoglycemia

**Nausea****Anorexia****Vomiting****Abdominal pain****Fatigue****Dizziness****Dyspepsia**

**Placebo****N=538**

**17  (1 severe)****2 ****7****7****4****4****3**

**Pramlintide****N=1179**

**51  (7 severe)****18 ****13****8****7****4****4**

## Most Nausea is Mild to ModeratePramlintide-Treated Type 1 Patientsin Long-Term Controlled Trials

**No nausea**
**49%**

**Mild**
**22%**

**Moderate**
**22%**

**Severe**
**7%**

## Nausea is Dose DependentType 1 Diabetes Long-Term Controlled Studies

**Pramlintide Dose**

**Incidence of Nausea (%)**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**0 (Placebo)**

**30/60 μg**

**60 μg**

**90 μg**

**70**

**80**

**90**

**100**

## Nausea Dissipates Over TimeType 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**

## Serious Treatment-EmergentAdverse Events (1% of Subjects)

**Placebo **

**Pramlintide **

**Type 1**

***Body System:***

**Events different between pramlintide and placebo **

## Assessment of Severe Hypoglycemiain 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 Serious****Adverse Events**

## 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 + Ins**

**Pbo + Insulin**

**n=538**

**n=1179**

## 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 + Ins**

**Pbo + Insulin**

**n=538**

**n=1179**

## Severe Hypoglycemia Annual Event Rate over TimeType 1 Diabetes

**Severe Hypoglycemia Annual Event Rate over Time****Type 1 Diabetes**

**1.6**

**3.2**

**1.1**

**1.0**

**1.0**

**0.6**

**0**

**1**

**2**

**3**

**4**

**5**

**Mean (SE)**

**Event**

**Rate ****per**

**Subject**

**Year**

**Pramlintide**** + Insulin****n=1179**

**Placebo +****Insulin****n=538**

**Pramlintide**** + Insulin****n=1025**

**Pramlintide**** + Insulin****n=641**

**Placebo +****Insulin****n=359**

**Weeks 0-4**

**Weeks 4-26 **

**Weeks 26-52 **

## Severe Hypoglycemia Annual Event Rate by DoseType 1 Diabetes

**Weeks 0-4**

**5**

**4**

**3**

**2**

**1**

**0**

**Placebo**
** ****+ 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 Per**

**Subject**

**Year**

## Risk for Severe HypoglycemiaDecreases over TimeType 1 Diabetes, All Patients

**Risk**

**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.**

## Risk for Severe HypoglycemiaDecreases over TimeType 1 Diabetes, 30 μg QID

**Placebo**

**Pramlintide**

**RT O’Neill *****Drug Information Journal*****; 21: 9-20, 1987.**

## Pramlintide AloneDoes Not Cause Hypoglycemia

**Normal volunteers did not become****hypoglycemic following ****10,000 μg**** dose**
**80x maximum recommended dose**

## Pramlintide Does Not Alter the Responseto 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**

## 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

**Pramlintide Benefits are Seen in Patients with****Type 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)**

**Mean****HbA****1C****(%)**

**0**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**3.0**

**3.5**

**4.0**

**4.5**

**Event Rate Per Subject Year**

**Weeks****0-4**

**Weeks****4-26**

**Severe Hypoglycemia**

## Other Safety ObservationsType 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**

## Pramlintide is Efficacious and Safein 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**

## 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**

## 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**

## 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/day****before meals**

## 
Risk/Benefit Summary

**Risk/Benefit Summary**

## 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 overcoming****these barriers**
**WE NEED NEW TOOLS **

## Risk of Current Insulin Therapy

**Risk of Current Insulin Therapy**

**% HbA****1c**** Reduction**

** ****Insulin Dose**
** ****Hypoglycemia**
** ****Weight Gain**

**Insulin Alone**

## Type 2 DiabetesPramlintide offers clear benefits outweighing expected,well recognized andmanageable risks

## Type 2 Diabetes —Adjunctive to Insulin Therapy

**Risk**
**Nausea**
**Mild, infrequent****and transient**
**Severe Hypoglycemia**
**No overall****increased risk**

**Management**
** **
**Good clinical care**
**Adjustment of****insulin dose**

**Pramlintide is safe**

## Pramlintide Overcomes Barriers and Challengesto Insulin Therapy in Type 2 Diabetes

**Barriers**
**Postprandial hyperglycemia**
**Weight gain**
**Hypoglycemia**
**Hyperinsulinemia**

**Benefits**
**Reduced postprandial glucose excursions**
**Weight loss**
**No overall****increased risk**
**Permits reduction****of insulin dose**

## Type 1 Diabetes Pramlintide offers clear benefits outweighing expected,well recognized andmanageable risks

## Risk
Nausea
Mild-moderate-severe
Dose-dependentand transient

**Nausea**
**Mild-moderate-severe**
**Dose-dependent****and transient**

**Management**
**Start therapy at****30 ****μ****g or less**

**Type 1 Diabetes —****Adjunctive to Insulin Therapy**

**Severe Hypoglycemia**
**Increased risk****upon initiation**
**Increased nausea/satiety**
**Dose-dependent**

**Start therapy at****30 ****μ****g or less**
**Adjustment of****insulin dose**

**Pramlintide can be used safely**

## Pramlintide Overcomes Barriers and Challengesto Insulin Therapy in Type 1 Diabetes 

**Barriers**
**Hypoglycemia**
**Weight gain**
**Postprandial hyperglycemia ****and glycemic swings**

**Benefits**
**No overall****increased risk**
**Possible reduction of risk post-initiation**
**Weight loss particularly****in overweight patients**
**Reduces postprandial glucose excursions **

## Is the Reduction in HbA1c Obtainedwith Pramlintide Worthwhile?

**Average reductions in HbA****1c**** of 0.3 – 0.7%****vs. insulin alone and 0.5 – 1.0% vs. baseline****are worthwhile**
**According to DCCT data a 0.5% reduction****in HbA****1c**** leads to ~ 30% decrease in risk****of retinopathy**

## Benefit of Pramlintide Therapyin Addition to Insulin

**To further reduce HbA****1c**** and attain****glycemic goals**
** **
**To control postprandial hyperglycemia****and associated glycemic swings**
**Minimize weight gain**

## Benefits of Pramlintide Therapyin 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 additive****to the actions of insulin to limit postprandial****glycemic excursions**

## Advantages of Addition ofPramlintide to Insulin Therapy

**Advantages of Addition of****Pramlintide to Insulin Therapy**

**% HbA****1c**** Reduction**

** ****Insulin Dose**
** ****Hypoglycemia**
** ****Weight Gain**

**Pramlintide + Insulin**
**Insulin Alone**

## The complementary actions of insulin and pramlintide form a potent binary therapeutic toolto lower postprandialplasma glucose

## Conclusion

**    **
**Amylin replacement with pramlintide represents a****novel and unique therapeutic advance that****fulfills a need for patients with****diabetes treated with insulin**