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Development of Therapeutic Agents Based on the GLP-1 Pathway

Development of Therapeutic Agents Based on the GLP-1 Pathway. Terry W. Sherraden, MD, FACE Tallahassee Endocrine Associates Tallahassee Florida. Emergence of Diabetes as a Multihormonal Disorder: A Historical Perspective. Insulin analogues. Human insulin. Pump therapy. Zinc insulin.

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Development of Therapeutic Agents Based on the GLP-1 Pathway

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

  2. Emergence of Diabetes as a Multihormonal Disorder: A Historical Perspective Insulin analogues Human insulin Pump therapy Zinc insulin NPH insulin Discovery Insulin b cells Amylin Pramlintide approved (2005) Discovery Amylin analogue Glucagon antagonists Discovery a cells Glucagon Exendin-4 and GLP-1 analogues Exenatide approved (2005) Discovery Lcells GLP-1 1925 1950 1975 2000 ©2006, ICHE

  3. 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. The Incretin Effect Creutzfeldt. Diabetologia. 1985;28:565. ©2006, ICHE

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

  5. Mammalian Proglucagon 31/32 62/63 109/110 124/125 Contains glucagon and 2 “glucagon-like” peptides Glucagon GLP-2 Glucagon GLP-1 GRPP SP-2 70/71 77 1 159/160 Arginine GRPP=glicentin-related pancreatic peptide GLP=glucagon-like peptide SP=spacer peptide Lysine Adapted from: Ørskov. J Biol Chem. 1989;264:12826. ©2006, ICHE

  6. The Incretins GLP-1: Glucagon-Like Peptide1 A G F S S V L G A H E T T D Y E S Q A K A K F L R I V E W G G GIP: Gastric Inhibitory Polypeptide Glucose-Dependent Insulinotropic Polypeptide A G F S I Y M K H Y E T I D A D S I Q Q N K A F G D L K N V L D K W W Q K T I N Q H Amino acids shown in yellow are homologous with the structure of glucagon. Courtesy of Daniel Drucker, MD. Drucker. Diabetes Care. 2003;26:2929. ©2006, ICHE

  7. 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) GLP-1: An Intestinal Hormone Drucker. Diabetes Care. 2003;26:2929. ©2006, ICHE

  8. Is the Incretin Effect Reduced in T2DM Compared With NGT? 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 NGT=normal glucose tolerance ©2006, ICHE Nauck. Diabetologia. 1986;29:46.

  9. Oral (50 g) IV (isoglycemic infusion) The Incretin Effect Is Reduced in T2DM Compared With NGT -Cell SecretoryResponse IncretinEffect 38.9 72.8 34.7 23.5 Insulin(mmol/L/min) Contributions of Incretin Factors (%) 30.0 11.3 Glucose: Nauck. Diabetologia. 1986;29:46. ©2006, ICHE NGT=normal glucose tolerance

  10. Release of GLP-1 Is Impaired in Patients With T2DM 20 * * * * NGT IGT T2DM * Breakfast * 15 * GLP-1 (pmol/L) 10 * 5 0 0 60 120 180 240 Time (min) *P<0.05 vs T2DM NGT=normal glucose tolerance IGT=impaired glucose tolerance Toft-Nielsen. J Clin Endocrinol Metab. 2001;86:3717; with permission. ©2006, ICHE

  11. FPG and PPG: Contribution to A1C Postprandial Fasting A1C (%) <7.3 70% 30% 7.3–8.4 50% 50% % Contributionto A1C 8.5–9.2 45% 55% 40% 60% 9.3–10.2 30% 70% >10.2 ©2006, ICHE Monnier. Diabetes Care. 2003;26:881.

  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. ©2006, ICHE

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

  14. Effect of GLP-1 on -Cell Apoptosis in Isolated Human Islets 18.9 20 Day 1 Day 3 15.5 P<0.01for days 3 and 5 Day 5 15 Apoptotic Nuclei(%) 8.9 10 6.1 5 0 Control GLP-1 ©2006, ICHE Farilla. Endocrinology. 2003;144:5149.

  15. 6-Week Subcutaneous GLP-1 Infusion Treatment Effects in 20 Patients With T2DM Saline GLP-1 Rx Effect(n=9*) (n=10) Baseline A1C (%) 8.9 9.2 A1C (%) +0.2 -1.3 -1.5% Weight (kg) -0.7 -1.9 -1.2 kg *One patient was excluded because no veins were accessible. Zander. Lancet. 2002;359:824. ©2006, ICHE

  16. 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 GLP-1 in Type 2 Diabetes DPP-IV=dipeptidyl peptidase IV Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56. ©2006, ICHE

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

  18. 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 Pharmacologic Approaches to Enhancing GLP-1 Action in Diabetes Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56. ©2006, ICHE

  19. 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 Pharmacologic Approaches to Enhancing GLP-1 Action in Diabetes Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56. ©2006, ICHE

  20. 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 Pharmacologic Approaches to Enhancing GLP-1 Action in Diabetes Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56. ©2006, ICHE

  21. Pharmacologic Agents ©2006, ICHE

  22. 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 Exenatide (Exendin-4) Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56. ©2006, ICHE

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

  24. 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) AMIGO Trial Results DeFronzo. Diabetes Care. 2005;28:1092. Buse. Diabetes Care. 2004;27:2628. Kendall. Diabetes Care. 2005;28:1083. ©2006, ICHE

  25. AMIGO 1: Efficacy Results (Exenatide + Metformin) Exenatide Placebo5 mcg BID10 mcg BID A1C (%) 30-week Δ +0.08 -0.40 -0.78 FPG (mg/dL) 30-week Δ+14.4 -7.2 -10.1 Weight (kg) 30-week Δ -0.3 -1.6 -2.8 DeFronzo. Diabetes Care. 2005;28:1092. ©2006, ICHE

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

  27. 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 AMIGO 1: Safety Results(Exenatide + Metformin) DeFronzo. Diabetes Care. 2005;28:1092. ©2006, ICHE

  28. AMIGO 2: Efficacy Results (Exenatide + Sulfonylurea) Exenatide Placebo5 mcg BID10 mcg BID A1C(%) 30-week Δ+0.12 -0.46 -0.86 FPG (mg/dL) 30-week Δ +7.24-5.43 -10.86 Weight (kg) 30-week Δ -0.6 -0.9 -1.6 ©2006, ICHE Buse. Diabetes Care. 2004;27:2628.

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

  30. 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 AMIGO 2: Safety Results SU=sulfonylurea Buse. Diabetes Care. 2004;27:2628. ©2006, ICHE

  31. AMIGO 3: Efficacy Results (Exenatide + Combination Therapy) Exenatide Placebo5 mcg BID10 mcg BID A1C (%) 30-week Δ+0.23 -0.55 -0.77 FPG (mg/dL) 30-week Δ +14 -9 -11 Weight (kg) 30-week Δ -0.9 -1.6 -1.6 Kendall. Diabetes Care. 2005;28:1083. ©2006, ICHE

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

  33. 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 AMIGO 3: Safety Results Kendall. Diabetes Care. 2005;28:1083. ©2006, ICHE

  34. 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 3 AMIGO Trials: Overview of Safety Results DeFronzo. Diabetes Care. 2005;28:1092. Buse. Diabetes Care. 2004;27:2628. Kendall. Diabetes Care. 2005;28:1083. ©2006, ICHE

  35. 3 AMIGO Trial ComparisonsExenatide (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. ©2006, ICHE

  36. 3 AMIGO Trial ComparisonsExenatide (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. ©2006, ICHE

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

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

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

  40. 3 AMIGO Trial ComparisonsExenatide (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. ©2006, ICHE

  41. 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 Exenatide’s Effects on First- and Second-Phase Insulin Secretion Fehse. J Clin Endocrinol Metab. 2005;90:5991. ©2006, ICHE

  42. SalineExenatideRatio Insulin (mU·min/L)* AUC0-10 min 212±38 655±116 3.1 AUC10-120 min 2611±355 6923±941 2.7 C-peptide (ng·min/L)* AUC0-10 min 26±3 52±6 2.0 AUC10-120 min 514±37 908±65 1.8 Restoration of Insulin Secretory Responses *Values are geometric least square (LS) mean ±SE. Fehse. J Clin Endocrinol Metab. 2005;90:5991. ©2006, ICHE

  43. 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 Liraglutide ©2006, ICHE

  44. 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 12 Weeks of Liraglutidevs Glimepiride in Type 2 Diabetes Madsbad. Diabetes Care. 2004;27:1335. ©2006, ICHE

  45. 12 Weeks of Liraglutidevs Glimepiride in Type 2 Diabetes Placebo-Adjusted Results Liraglutide 0.45 mg0.60 mg0.75 mgGlimepiride n=27 n=30 n=28 n=26 A1C (%) -0.30 -0.70* -0.75* -0.74* FPG (mg/dL) -6.3 -38.6* -32.8* -46.8* Weight (kg) -1.20* 0.27 -0.39 0.94 *P<0.02 ©2006, ICHE Madsbad. Diabetes Care. 2004;27:1335.

  46. 12 Weeks of Liraglutidevs Glimepiride in Type 2 Diabetes 0.45 mg 0.75 mg 0.60 mg Glimepiride Changes in A1C Changes in FPG Madsbad. Diabetes Care. 2004;27:1335. ©2006, ICHE

  47. 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 Safety Results: 12 Weeks of Liraglutide vs Glimepiride Madsbad. Diabetes Care. 2004;27:1335. ©2006, ICHE

  48. 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 Vildagliptin ©2006, ICHE

  49. 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 12 Weeks of Vildagliptin Therapy vs Placebo inPatients Taking Metformin Ahrén. Diabetes Care. 2004;27:2874. ©2006, ICHE

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

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