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©2006, ICHE Development of Therapeutic Agents Based on the GLP-1 Pathway Terry W. Sherraden, MD, FACE Tallahassee Endocrine Associates Tallahassee Florida.

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Presentation on theme: "©2006, ICHE Development of Therapeutic Agents Based on the GLP-1 Pathway Terry W. Sherraden, MD, FACE Tallahassee Endocrine Associates Tallahassee Florida."— Presentation transcript:

1 ©2006, ICHE Development of Therapeutic Agents Based on the GLP-1 Pathway Terry W. Sherraden, MD, FACE Tallahassee Endocrine Associates Tallahassee Florida

2 ©2006, ICHE Emergence of Diabetes as a Multihormonal Disorder: A Historical Perspective  cells  cells Discovery Insulin analogues Pump therapy Human insulin Zinc insulin NPH insulin Insulin Amylin Discovery Amylin analogue Pramlintide approved (2005) Glucagon antagonists Discovery Glucagon GLP-1 Exenatide approved (2005) Exendin-4 and GLP-1 analogues Discovery L cells

3 ©2006, ICHE The Incretin Effect Ingested glucose results in a more robust insulin response than glucose administered intravenously, indicating the presence of substances within the gastrointestinal tract that stimulate insulin release in a glucose-dependent manner. Creutzfeldt. Diabetologia. 1985;28:565.

4 ©2006, ICHE Definition of Incretins “Gut-derived factors that increase glucose-stimulated insulin secretion” In ● cre ● tin Intestine Secretion Insulin Creutzfeldt. Diabetologia. 1985;28:565.

5 Lysine Arginine 159/ / / / /32 70/71 GLP-2 SP-2 GLP-1 Glucagon GRPP=glicentin-related pancreatic peptide GLP=glucagon-like peptide SP=spacer peptide Adapted from: Ørskov. J Biol Chem. 1989;264: GRPP Mammalian Proglucagon Contains glucagon and 2 “glucagon-like” peptides Glucagon ©2006, ICHE

6 The Incretins Y A E G T F I S D Y S I A M D K I H Q Q D F V N W L L A Q K G K K N D W K H NQ T I GIP : Gastric Inhibitory Polypeptide Glucose-Dependent Insulinotropic Polypeptide H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R G GLP-1 : Glucagon-Like Peptide 1 Amino acids shown in yellow are homologous with the structure of glucagon. Courtesy of Daniel Drucker, MD. Drucker. Diabetes Care. 2003;26:2929.

7 ©2006, ICHE GLP-1: An Intestinal Hormone Secreted from L cells in the intestinal mucosa after meals Effects –Stimulates insulin secretion –Suppresses glucagon secretion –Delays gastric emptying –Enhances satiety –Enhances  -cell mass/replication in animals Rapidly degraded by the protease dipeptidyl peptidase IV (DPP-IV) Drucker. Diabetes Care. 2003;26:2929.

8 To determine incretin effect in T2DM Infuse glucose to maintain glycemia at same levels as following a 50-g oral challenge Record  -cell secretory responses to oral and IV administration of glucose –Insulin and C-peptide Calculate ratio Compare healthy with T2DM Is the Incretin Effect Reduced in T2DM Compared With NGT? Nauck. Diabetologia. 1986;29:46. NGT=normal glucose tolerance ©2006, ICHE

9 Nauck. Diabetologia. 1986;29:46. The Incretin Effect Is Reduced in T2DM Compared With NGT Incretin Effect Insulin (mmol/L/min) Glucose: IV (isoglycemic infusion) Oral (50 g)  -Cell Secretory Response NGT=normal glucose tolerance Contributions of Incretin Factors (%) ©2006, ICHE

10 NGT IGT T2DM Breakfast * * * * * ** * Time (min) Toft-Nielsen. J Clin Endocrinol Metab. 2001;86:3717; with permission. Release of GLP-1 Is Impaired in Patients With T2DM GLP-1 (pmol/L) *P<0.05 vs T2DM NGT=normal glucose tolerance IGT=impaired glucose tolerance ©2006, ICHE

11 FPG and PPG: Contribution to A1C Monnier. Diabetes Care. 2003;26: % 60% 55% 50% 30% 40% 45% 50% 70% FastingPostprandial > – – –8.4 <7.3 A1C (%) % Contribution to A1C ©2006, ICHE

12 Enhances responsiveness of the  cell to glucose Improves the dynamics of the insulin response Stimulates  -cell transcription Reduces  -cell apoptosis Effects of GLP-1 on  Cells Ahrén. Diabetes Care. 2003;26:2860. Farilla. Endocrinology. 2002;143:4397.

13 ©2006, ICHE ↑  -Cell Mass: 1- to 6-fold increase ↑  -Cell Proliferation: 1.4-fold increase ↓  -Cell Apoptosis: 3.6-fold decrease Effect of GLP-1 on  Cells in Zucker Diabetic Fatty Rats AUC: Glucose (day 6) AUC: Insulin (day 6) GLP-1 Control GLP-1 infusion Control 65% 100% 240% 100% Farilla. Endocrinology. 2002;143:4397.

14 Farilla. Endocrinology. 2003;144:5149. Effect of GLP-1 on  -Cell Apoptosis in Isolated Human Islets Apoptotic Nuclei (%) Control P<0.01 for days 3 and 5 GLP-1 Day 5 Day 3 Day ©2006, ICHE

15 6-Week Subcutaneous GLP-1 Infusion Treatment Effects in 20 Patients With T2DM SalineGLP-1Rx Effect (n=9*)(n=10) Baseline A1C (%)  A1C (%) %  Weight (kg) kg Zander. Lancet. 2002;359:824. *One patient was excluded because no veins were accessible.

16 ©2006, ICHE GLP-1 in Type 2 Diabetes Glucoregulatory hormone secreted by endocrine cells of intestine after a meal –Functions as an incretin hormone Biologic activities include the following: –Stimulation of glucose-dependent insulin secretion and insulin biosynthesis –Inhibition of glucagon secretion, gastric emptying, and food intake Levels are reduced in type 2 diabetes Inactivated by the enzyme DPP-IV Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56. DPP-IV=dipeptidyl peptidase IV

17 ©2006, ICHE Pharmacologic Approaches to Enhancing GLP-1 Action in Diabetes Chronic infusion of rHu GLP-1 GLP-1 receptor agonists DPP-IV inhibitors rHu=recombinant human DPP-IV=dipeptidyl peptidase IV Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56.

18 ©2006, ICHE Pharmacologic Approaches to Enhancing GLP-1 Action in Diabetes Chronic infusion of rHu GLP-1 –Not a desirable therapeutic approach –Necessary to achieve steady state because of short half-life (1–2 minutes) of GLP-1 –Parenteral GLP-1 rapidly degraded Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56.

19 ©2006, ICHE Pharmacologic Approaches to Enhancing GLP-1 Action in Diabetes GLP-1 receptor agonists –Mimetics Possess physiologic characteristics and biologic activity of native GLP-1 but resist degradation by DPP-IV Exenatide (exendin-4) Analogues –Half-lives increased by modification of rHu GLP-1 to resist DPP-IV degradation –Liraglutide, albugon, CJC-1131, ZP10 Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56.

20 ©2006, ICHE Pharmacologic Approaches to Enhancing GLP-1 Action in Diabetes DPP-IV inhibitors –Advantage of oral administration –Improve glucose tolerance and increase insulin release –Multiple targets may lead to unwanted effects on immune function Possible safety issues Vildagliptin, sitagliptin, and saxagliptin Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56.

21 ©2006, ICHE Pharmacologic Agents Drug Class, Research Name Generic NameManufacturerStatus DPP-IV Inhibitors LAF237 MK-0431 BMS Vildagliptin Sitagliptin Saxagliptin Novartis Merck BMS Phase 3 GLP-1 Receptor Agonists Mimetics Exendin-4 Analogues NN2211 CJC-1131 ZP10 Albugon Exenatide Liraglutide Not determined Amylin/Lilly Novo Nordisk ConjuChem Sanofi-Aventis Human Genome Sciences FDA-approved Phase 2

22 ©2006, ICHE Exenatide (Exendin-4) 39–amino acid GLP-1 receptor agonist >50% homology with native GLP-1 Glucoregulatory actions similar to GLP-1 Resistant to degradation activity of DPP-IV because of different amino acid sequence –Longer duration of action in vivo Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56.

23 GLP-1(7–36) and Exendin-4 (Structures) HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS Exendin-4 GLP-1(7–36) Eng. J Biol Chem. 1992;267:7402. ©2006, ICHE

24 AMIGO Trial Results Acronym for AC2993 (early name for exenatide) Diabetes Management for Improving Glucose Outcomes –April 2005 approval of exenatide for treatment of T2DM based on results of these 3 trials Exenatide compared with placebo in the following groups: –AMIGO 1: Patients taking metformin –AMIGO 2: Patients taking a sulfonylurea –AMIGO 3: Patients taking combination therapy (metformin + sulfonylurea) DeFronzo. Diabetes Care. 2005;28:1092. Buse. Diabetes Care. 2004;27:2628. Kendall. Diabetes Care. 2005;28:1083.

25 ©2006, ICHE Placebo5 mcg BID 10 mcg BID A1C (%) 30-week Δ FPG (mg/dL) 30-week Δ Weight (kg) 30-week Δ AMIGO 1: Efficacy Results (Exenatide + Metformin) Exenatide DeFronzo. Diabetes Care. 2005;28:1092.

26 ©2006, ICHE AMIGO 1: Efficacy Results (Exenatide + Metformin) DeFronzo. Diabetes Care. 2005;28:1092. Changes in A1C Changes in FPG Placebo 5 mcg 10 mcg Placebo 5 mcg 10 mcg

27 ©2006, ICHE AMIGO 1: Safety Results (Exenatide + Metformin) Incidence of serious and severe adverse events (AEs) was low and evenly distributed among treatment groups Nausea was the most frequently reported severe adverse reaction –Occurred more frequently in exenatide groups –Mild or moderate in 10-mcg exenatide group No reported cases of severe hypoglycemia Weight loss was independent of nausea DeFronzo. Diabetes Care. 2005;28:1092.

28 ©2006, ICHE AMIGO 2: Efficacy Results (Exenatide + Sulfonylurea) Placebo5 mcg BID10 mcg BID A1C (%) 30-week Δ FPG (mg/dL) 30-week Δ Weight (kg) 30-week Δ Exenatide Buse. Diabetes Care. 2004;27:2628.

29 ©2006, ICHE AMIGO 2: Efficacy Results (Exenatide + Sulfonylurea) Buse. Diabetes Care. 2004;27:2628. Changes in A1C Changes in FPG Placebo 5 mcg 10 mcg Placebo 5 mcg 10 mcg

30 ©2006, ICHE AMIGO 2: Safety Results Low incidence of serious AEs in all groups Nausea was the most frequently reported –Low incidence of severe nausea –Peaked in early weeks of treatment –Caused few to no withdrawals No cases of severe hypoglycemia –Hypoglycemia dose dependent and more frequent in exenatide-treated patients –Likely background susceptibility to SU and not due to exenatide Buse. Diabetes Care. 2004;27:2628. SU=sulfonylurea

31 ©2006, ICHE Placebo5 mcg BID10 mcg BID A1C (%) 30-week Δ FPG (mg/dL) 30-week Δ Weight (kg) 30-week Δ AMIGO 3: Efficacy Results (Exenatide + Combination Therapy) Exenatide Kendall. Diabetes Care. 2005;28:1083.

32 ©2006, ICHE AMIGO 3: Efficacy Results (Exenatide + Combination Therapy) Kendall. Diabetes Care. 2005;28:1083. Changes in A1C Changes in FPG Placebo 5 mcg 10 mcg Placebo 5 mcg 10 mcg

33 ©2006, ICHE AMIGO 3: Safety Results Incidence of serious and severe AEs was low and evenly distributed among groups Nausea most common severe AE –Dose dependent –Higher incidence during initial weeks of treatment –Not correlated with reported weight loss –Associated with low incidence of withdrawals Mild or moderate hypoglycemia –More common in exenatide groups –Influenced by background dose of SU, dose of exenatide, and ambient level of glycemia Kendall. Diabetes Care. 2005;28:1083.

34 ©2006, ICHE 3 AMIGO Trials: Overview of Safety Results Most commonly reported AEs were gastrointestinal in nature Nausea was the most frequently reported AE in all 3 trials Low incidence of severe hypoglycemia Reported weight loss was independent of nausea DeFronzo. Diabetes Care. 2005;28:1092. Buse. Diabetes Care. 2004;27:2628. Kendall. Diabetes Care. 2005;28:1083.

35 ©2006, ICHE 3 AMIGO Trial Comparisons Exenatide (10 mcg BID) Added to Sulfonylurea, Metformin, or Combination Therapy Change in A1C Change in FPG % mg/dL Absolute Change Placebo- Adjusted Change Placebo-Adjusted Change DeFronzo. Diabetes Care. 2005;28:1092. Buse. Diabetes Care. 2004;27:2628. Kendall. Diabetes Care. 2005;28:1083.

36 ©2006, ICHE 3 AMIGO Trial Comparisons Exenatide (10 mcg BID) Added to Sulfonylurea, Metformin, or Combination Therapy Change in A1C Absolute Change Placebo- Adjusted Change DeFronzo. Diabetes Care. 2005;28:1092. Buse. Diabetes Care. 2004;27:2628. Kendall. Diabetes Care. 2005;28:1083.

37 ©2006, ICHE 3 AMIGO Trial Comparisons Exenatide (10 mcg BID) Added to Sulfonylurea, Metformin, or Combination Therapy Change in FPG Absolute Change Placebo- Adjusted Change DeFronzo. Diabetes Care. 2005;28:1092. Buse. Diabetes Care. 2004;27:2628. Kendall. Diabetes Care. 2005;28:1083.

38 ©2006, ICHE 3 AMIGO Trial Comparisons Exenatide (10 mcg BID) Added to Sulfonylurea, Metformin, or Combination Therapy Change in Weight Absolute Change Placebo- Adjusted Change DeFronzo. Diabetes Care. 2005;28:1092. Buse. Diabetes Care. 2004;27:2628. Kendall. Diabetes Care. 2005;28:1083.

39 ©2006, ICHE 3 AMIGO Trial Comparisons Exenatide (10 mcg BID) Added to Sulfonylurea, Metformin, or Combination Therapy Incidence of Nausea With Exenatide Compared With Placebo DeFronzo. Diabetes Care. 2005;28:1092. Buse. Diabetes Care. 2004;27:2628. Kendall. Diabetes Care. 2005;28:1083. PLB PLB=placebo SU Met Combo

40 ©2006, ICHE 3 AMIGO Trial Comparisons Exenatide (5 mcg or 10 mcg BID) Added to Sulfonylurea, Metformin, or Combination Therapy Incidence of Nausea With Exenatide Compared With Placebo DeFronzo. Diabetes Care. 2005;28:1092. Buse. Diabetes Care. 2004;27:2628. Kendall. Diabetes Care. 2005;28:1083.

41 ©2006, ICHE Exenatide’s Effects on First- and Second-Phase Insulin Secretion Purpose –To determine the effect of exenatide on biphasic insulin secretory responses Study design –Patients randomized to receive exenatide or saline and compared with healthy controls Primary end point –Plasma insulin, plasma C-peptide, and insulin secretion rate Fehse. J Clin Endocrinol Metab. 2005;90:5991.

42 ©2006, ICHE Restoration of Insulin Secretory Responses Saline Exenatide Ratio Insulin (mU·min/L)* AUC 0-10 min 212±38 655± AUC min 2611± ± C-peptide (ng·min/L)* AUC 0-10 min 26±3 52±6 2.0 AUC min 514±37 908± Fehse. J Clin Endocrinol Metab. 2005;90:5991. *Values are geometric least square (LS) mean ±SE.

43 ©2006, ICHE Liraglutide A long-acting, acylated GLP-1 analogue –Acts as a full GLP-1 receptor agonist –Stimulates insulin production and release –Inhibits glucagon release and thus decreases glucose levels Currently in phase 3 clinical trials Available as subcutaneous injection

44 ©2006, ICHE 12 Weeks of Liraglutide vs Glimepiride in Type 2 Diabetes Purpose –To assess the efficacy and safety of liraglutide after 12 weeks in patients with T2DM Trial design –Double-blind, randomized, parallel-group, placebo-controlled, with an open-label comparator arm –Random assignments to 1 of 5 liraglutide groups, placebo, or glimepiride Primary end point: A1C after 12 weeks Madsbad. Diabetes Care. 2004;27:1335.

45 12 Weeks of Liraglutide vs Glimepiride in Type 2 Diabetes Placebo-Adjusted Results 0.45 mg 0.60 mg 0.75 mg Glimepiride n=27 n=30 n=28 n=26 A1C (%) * -0.75* -0.74* FPG (mg/dL) * -32.8* -46.8* Weight (kg) -1.20* Madsbad. Diabetes Care. 2004;27:1335. Liraglutide *P<0.02 ©2006, ICHE

46 12 Weeks of Liraglutide vs Glimepiride in Type 2 Diabetes Madsbad. Diabetes Care. 2004;27: mg 0.60 mg 0.75 mg Glimepiride Changes in A1C Changes in FPG

47 ©2006, ICHE Safety Results: 12 Weeks of Liraglutide vs Glimepiride Very low risk of hypoglycemia Headache and nausea were most frequent AEs –Transient; mild to moderate; resolved without intervention Gastrointestinal AEs –Transient –Dosage related –Did not cause patients to withdrawal from treatment Madsbad. Diabetes Care. 2004;27:1335.

48 ©2006, ICHE Vildagliptin A DPP-IV inhibitor –Improves glucose tolerance and insulin response to oral glucose in patients with T2DM Available as oral formulation Will provide a once-daily treatment option for patients with T2DM Currently completing phase 3 clinical trials

49 ©2006, ICHE 12 Weeks of Vildagliptin Therapy vs Placebo in Patients Taking Metformin Purpose –To assess efficacy of vildagliptin in patients with T2DM taking metformin Trial design –12-week, randomized, double-blind, placebo- controlled trial, with a 40-week extension –Patients continuing metformin treatment –Random assignments to addition of placebo or vildagliptin Primary end points: A1C and FPG after 12 and 52 weeks of therapy Ahrén. Diabetes Care. 2004;27:2874.

50 ©2006, ICHE 12 Weeks of Vildagliptin Therapy vs Placebo in Patients Taking Metformin Absolute Change in A1C Absolute Change in FPG % mg/dL Ahrén. Diabetes Care. 2004;27:2874.

51 Vildagliptin at 12 Weeks in Patients Taking Metformin: Safety Incidence of AEs in vildagliptin-treated group similar to that seen in placebo group Few severe AEs reported Low incidence of hypoglycemia Effects on blood pressure merit additional clinical study Ahrén. Diabetes Care. 2004;27:2874. ©2006, ICHE

52 Summary Incretin hormones stimulate insulin release in a glucose-dependent manner. The incretin hormone GLP-1 plays a major role in reducing postprandial glucose excursions. GLP-1 and the incretin effect are diminished in type 2 diabetes. Not applicable in type 1. GLP-1 has a short half-life (~90 seconds). GLP-1 enhancement therapy with either a GLP-1 mimetic, GLP-1 analogue, or DPP-IV inhibitor has shown very promising results in clinical trials and initial general clinical practice. ©2006, ICHE


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