Pramlintide & Weight. Diane M Karl MD. The Endocrine Clinic & Oregon Health & Science University Portland, Oregon

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1 Pramlintide & Weight Diane M Karl MD The Endocrine Clinic & Oregon Health & Science University Portland, Oregon

2 Conflict of Interest Speakers Bureau: Amylin Pharmaceuticals Consultant: sanofi-aventis Grant support: Amylin Pharmaceuticals, sanofi-aventis

3 Lecture outline Amylin/pramlintide physiology Early clinical trials & weight Limitations of prandial insulin Recent studies T2DM Non-diabetes

4 Amylin: the hormone Amylin Reported in amino acid peptide Co-located and co-secreted with insulin from pancreatic ß-cells amylin insulin Unger and Foster. Williams Textbook of Endocrinology, 1992.

5 Insulin and Amylin Co-secreted 30 Meal Meal Meal Plasma amylin (pm) Without Diabetes n = Plasma insulin (pm) am 12 noon 5 pm Midnight 0 Insulin Amylin Time Koda et al, Diabetes. 1995; 44 (s1): 23BA. Weyer et al. Curr Pharm Des. 2001;7:

6 Amylin: A Neuroendocrine Hormone N N Amylin binding sites in the brain dorsal raphe C C Amylin Receptor Identified nucleus accumbens area postrema Beaumont K et al. Mol Pharm. 1993; 44: Muff R, et al. Endocrinology. 1999; 140:

7 Insulin and Amylin: Complementary Hormones Brain Satiety Liver Glucagon Gastric Emptying Pancreas Amylin Insulin + Plasma Glucose Glucose Disposal Tissues

8 Amylin Reduces Food Intake In Animals Food Intake (% of control) Intraperitoneal amylin dose (µg/kg) Bhavsar et al, Physiology and Behavior. 1998; 64(4):

9 Amylin Is Deficient in Diabetes 20 Meal Plasma amylin (pm) Without Diabetes 5 Insulin-Using Type 2 Type Time after Sustacal meal (min) Fineman et al, Diabetologia. 1996; 39 (S1): A149. Kruger et al. Diabetes Educ. 1999; 1999:

10 Pramlintide: Synthetic Amylin Analog Specifically engineered to overcome human amylin tendency to : Aggregate, adhere to surfaces Form insoluble particles and amyloid fibrils Potency equal to or greater than human amylin Human amylin Pramlintide (25, 28, 29 Pro-h-amylin)

11 Reduced food intake with pramlintide T2DM, n=11 (crossover) Chapman et al. Diabetologia 2005;48:

12 Pramlintide Therapy in Type 2 Diabetes Pre-registration trials All Patients, Recommended Dose Baseline: Change in % HbA 1c Change in Insulin Use (%) Change in Weight (lb) Week 4 Week 13 Week 26 Week 4 Week 13 Week 26 Week 4 Week 13 Week Placebo + Insulin (N=284) Pramlintide Recommended Dose + Insulin (N=292) Data on file, Amylin Pharmaceuticals, Inc.

13 Pramlintide Therapy in Type 1 Diabetes Pre-registration trials All Patients, Recommended Doses Baseline: Change in % HbA 1c Change in Insulin Use (%) Change in Weight (lb) Week 4 Week 13 Week Week 4 Week 13 Week Week 4 Week 13 Week 26 Placebo + Insulin (N=538) Pramlintide Recommended Doses + Insulin (N=716) Data on file, Amylin Pharmaceuticals, Inc.

14 Pramlintide + Insulin in T1DM Weight Effect by BMI Weight Change from Baseline at Week BMI 23 kg/m 2 BMI kg/m 2 BMI 27 kg/m 2 lbs 0 n=23 n=26 n=35 n=46-2 n= Data on file, Amylin Pharmaceuticals Inc. Insulin + Placebo Insulin + Pramlintide (60 µg TID) n=40

15 Limitations of prandial insulin

16 Treating to Target in Type 2 Diabetes (4T) Study Study Design N=708 T2DM patients Taking metformin + sulfonylurea Mean age 62, median duration DM 9 years Mean BMI 29.8 kg/m 2 Mean A1c 8.5% Randomized to add insulin as: Basal insulin (detemir) 1 or 2x daily Premixed insulin (aspart/protamine-aspart) 2x daily Prandial insulin (aspart) 3x daily Titration of dose by computerized system to: mg/dl FPG and pre-prandial mg/dl post-prandial 1 year follow-up on assigned treatment; 3 year follow-up after patients with A1c >6.5% at 1 year had each regimen intensified Holman RR et al. N Engl J Med 2007;357: Holman RR et al. N Engl J Med 2009;361:

17 4T Study 1-year results Basal 1-2x Premixed 2x Prandial 3x A1c % weight kg Hypoglycemia Mean number of events confirmed <56 mg/dl or severe per patient per year Holman RR et al. N Engl J Med 2007;357:

18 4T Study 3-year results Basal 1-2x Premixed 2x Prandial 3x A1c % weight kg Hypoglycemia Mean number of events confirmed <56 mg/dl or severe per patient per year Holman RR et al. N Engl J Med 2009;361:

19 A1c over 3 years in 4T Median±95% confidence interval Overall 6.9% (6.8 to 7.1) Biphasic ±prandial Prandial ±basal Basal ±prandial Holman RR et al. N Engl J Med 2009;361:

20 Body weight over 3 years in 4T Median±95% confidence interval Biphasic ±prandial Prandial ±basal Basal ±prandial Holman RR et al. N Engl J Med 2009;361:

21 DCCT Weight Gain Conventionally Treated Group 30 Intensively Treated Group Mean change weight (kg) Quartile of Weight Gain Purnell, et al. JAMA. 1998;280:

22 Additional pramlintide studies Currently approved indication: Pramlintide plus prandial insulin Approaches under investigation: Pramlintide with basal insulin Pramlintide vs placebo Pramlintide vs prandial aspart Pramlintide in obesity without diabetes

23 Three studies of pramlintide added to insulin Clinical Practice Concurrent Rx Basal-bolus Basal insulin Basal insulin insulin±oad ±OAD ±OAD Study treatment P 120 mcg P 60/120 mcg P 60/120 mcg vs baseline vs PLBO vs rapid insulin Duration of Rx (wk) N of subjects BMI (kg/m 2 ) Duration of DM (yr) A1c baseline (%) A1c (%) Wt (kg) INSTEAD

24 Pramlintide added to basal-bolus therapy study 6-month open-label clinical experience 7-point self-monitored glucose profiles 230 Baseline 6 Months Glucose mg/dl Mean+ SE acb pcb acl pcl acd pcd hs A1c 8.3% A1c -0.6% Wt -2.8 kg Insulin -6.4% P <0.05 Karl D et al. Diab Tech Ther 2007;9: 191-9

25 Three studies of pramlintide added to insulin Clinical Practice Concurrent Rx Basal-bolus Basal insulin Basal insulin insulin±oad ±OAD ±OAD Study treatment P 120 mcg P 60/120 mcg P 60/120 mcg vs baseline vs PLBO vs rapid insulin Duration of Rx (wk) N of subjects BMI (kg/m 2 ) Duration of DM (yr) A1c baseline (%) A1c (%) Wt (kg) INSTEAD

26 Pramlintide added to basal insulin study 4-months treatment compared with placebo 7-point self-monitored glucose profiles Glucose mg/dl Placebo Mean ± SE P<0.01 Breakfast Lunch Dinner Bedtime Baseline Week 16 Pramlintide Mean ± SE P<0.005 Breakfast Lunch Dinner Bedtime Baseline Week 16 Riddle M et al. Diabetes Care 2007;30:

27 Pramlintide added to titrated basal insulin 4-months treatment compared with placebo Baseline A1c 8.5 ± 0.1% 8.5 ± 0.1% Change of A1c A1c % Mean + SE Placebo + glargine -0.3% ± 0.1 ITT LOCF p < Pramlintide + glargine Riddle M et al. Diabetes Care 2007;30: Weeks

28 Pramlintide added to titrated basal insulin 4-months treatment compared with placebo Baseline weights 103 ± 1.8 kg 103 ± 1.7 kg Change of weight Placebo + glargine kilograms Mean + SE ± 0. 4 kg ITT LOCF p < Weeks Pramlintide + glargine Riddle M et al. Diabetes Care 2007;30:

29 Three studies of pramlintide added to insulin Clinical Practice Concurrent Rx Basal-bolus Basal insulin Basal insulin insulin±oad ±OAD ±OAD Study treatment P 120 mcg P 60/120 mcg P 60/120 mcg vs baseline vs PLBO vs rapid insulin Duration of Rx (wk) N of subjects BMI (kg/m 2 ) Duration of DM (yr) A1c baseline (%) A1c (%) Wt (kg) INSTEAD

30 Baseline Characteristics INSTEAD trial Data are mean ± SD, except where indicated PRAM n=56 RAI n=56 Sex (Male / Female; %) 61 / / 34 Age (y) 55 ± ± 10 Duration of diabetes (y) 10 ± 7 9 ± 6 Body weight (kg) 108 ± ± 18 BMI (kg/m 2 ) 36 ± 6 36 ± 6 A1C (%) 8.2 ± ± 0.8 FPG (mg/dl) 155 ± ± 50 Prior OAD use (MET / SFU / TZD; %) 79 / 70 / / 61 / 39 Prior insulin use (Yes; %) Baseline insulin use (U/day) 20 ± ± 12 Riddle M et al. Diabetes Care 2009;32:

31 Pramlintide added to titrated basal insulin 6-months treatment compared with rapid-acting insulin ) L d / ) ( m g g k G( P Fe n i l e s a B mg/dl m o r F kg e g n a h C FPG Weight Time (weeks) RAI PRAM % RAI PRAM units/day 9.0 RAI 8.5 PRAM RAI Initiation A1C Insulin Use Time (weeks) RAI total RAI basal PRAM Riddle MC et al. Diabetes Care 2009;32:

32 Pramlintide in non diabetes? Reduced food intake in animal studies Reduced food intake in buffet cross-over

33 Pramlintide Dose-Escalation Study Design Randomized, double-blind, placebo-controlled, multicenter study in obese subjects: Without type 2 diabetes (N = 160) With type 2 diabetes, treated with diet and exercise or metformin (N = 44) Study treatment: 16 weeks Pramlintide was initiated at 60 µg TID and escalated in 30-µg increments as tolerated up to 240 µg TID No lifestyle intervention Follow-up: 8 weeks Subjects were monitored for 8 weeks following treatment discontinuation Pbo Lead-In (1 wk) Escalation (4 wk) Maintenance (12 wk) Pramlintide or Placebo 120, 180 or 240 mg TID Follow-Up (8 wk) (No Pramlintide) Time (wk) Aronne L, et al. J Clin Endocrinol Metab 2007;92:

34 Pramlintide Elicited Reductions in Body Weight Regardless of Presence or Absence of Diabetes Placebo Pramlintide Without Type 2 Evaluable Mixed effects model With Type 2 Evaluable Mixed effects model 1 Escal Maintenance Follow-up 1 Escal Maintenance Follow-up 0 0 kg Time (wk) kg Time (wk) Aronne et al. J Clin Endocrinol Metab 2007;92: Mean±SE at Wk 16; P<0.01; P<0.001 compared to placebo; Evaluable N = 145; Mixed effects model N = 204

35 Pramlintide Reduced Body Weight Independent of Nausea Placebo (n = 67) Pramlintide (n = 137) Cumulative Incidence of Nausea (ITT) Placebo Lead-In 50 Escalation Maintenance Pramlintide nausea Pramlintide no nausea Weight Effect by Nausea Occurrence 1 Evaluable Escal Maintenance Follow-up Mixed effects model % with nausea kg Week of Study Time (wk) Aronne et al. J Clin Endocrinol Metab 2007;92: Evaluable: Nausea n = 37; No nausea n = 60 Mixed effects model Nausea n = 52; No nausea n = 85

36 Study Design Main Study and Extension 4-mo double-blind main study: Randomized, placebo-controlled, dose-ranging, multicenter study in obese subjects (N = 408) Three SC injections of study medication per day, 15 min prior to major meals Pramlintide BID regimen included placebo 15 min prior to midday meal All subjects participated in structured lifestyle intervention (LSI) encompassing diet, exercise and behavior modification (LEARN ) 8-mo single-blind extension: All subjects (N = 209) continued with their pre-existing regimens during the placebo- controlled extension Throughout extension LSI was geared towards weight maintenance Placebo Lead-In Double-blind Study 360 µg BID 240 µg BID 120 µg BID 360 µg TID 240 µg TID 120 µg TID Placebo TID Weight loss LSI Smith S.R., et. al. Diabetes Care 2008; 31: Single-blind Extension Month Extension - Weight maintenance LSI

37 Placebo 120 m g 240 m g 360 m g 1 0 Pramlintide in obese non-diabetic subjects in conjunction with life-style intervention Double-blind study BID dosing Evaluable Single-blind extension ITT-LOCF 1 0 Double-blind study TID dosing Evaluable Single-blind extension ITT-LOCF kg -4-5 kg Number of Subjects Placebo 120 µg BID 240 µg BID 360 µg BID Time (mo) Smith et al. Diabetes Care. 2008;31: Number of Subjects Placebo 120 µg TID 240 µg TID 360 µg TID Time (mo) Mean ± SE; P<0.05; P<0.01 compared to placebo; Significance is indicated only at 4-mo and 12-mo.

38 Proportion of Evaluable Subjects Achieving 5% and 10% Weight Loss by Month % Weight Loss % 60 57%57% 50 44% 41% % 18% Pbo BID TID BID TID BID TID P<0.05 compared to placebo % Weight Loss % 43% 40 35% 30 24% 22% 20 12% 8% 10 0 Pbo BID TID BID TID BID TID Smith et al. Diabetes Care. 2008;31:

39 Summary The amylin analog pramlintide used in conjunction with meal-time insulin can improve glucose control, often in association with weight loss Limitations of relying on prandial insulin for glucose control include weight gain and hypoglycemia Studies using pramlintide in T2DM added to basal insulin and in obese non-diabetic individuals suggest possible benefits which deserve further study

40 Thank you for your attention!