Section II: Benefit-Risk Management Principles and Practices
Chapter 6: The Impact of Preclinical Planning and Study Outcome on the Risk Management of Biologicals
96
Appendix 6-1
Example and Case Study: Early Toxicology Assessment for a Hypothetical Novel Glucagon-like Peptide-1 Analog
Target Description/Indication/Mechanism
Molecule—Glucagon-like peptide-1 (GLP-1) is a single molecule, 30-amino acid peptide that binds with activity to either
GIP or GLP-1 receptors. It is secreted from gut endocrine L-cells in a glucose-dependent manner.
Pharmacology—GLP-1 is an incretin in normal physiology and a potent stimulant of insulin synthesis and release and beta
cell mass. It inhibits glucagon secretion, slows gastric emptying and has an anorectic effect. These actions lower blood
glucose in both normal subjects and in patients with type 2 diabetes.
Known Issue—The side effects of GLP-1 receptor agonists mimic the pharmacology of native GLP-1. Intravenous or
subcutaneous administration of GLP-1 causes nausea and vomiting in a dose-dependent manner the doses above which
GLP-1 causes GI side effects are higher than those needed to regulate blood glucose. May delay gastric emptying. May
alter PK of drugs that require rapid GI absorption. Hypoglycemia caused by GLP-1 agonists is rare
Target Population—Type 2 diabetics not reaching goal with current GLP-1 agonist therapies.
Target Distribution: Ubiquitously Expressed
Receptor location • Islets, stomach, small intestine, adipose tissue, adrenal cortex, lung, pituitary, heart, testis,
bone, and brain
Islets
• Stimulates glucose-induced insulin secretion
• Increase insulin gene transcription and biosynthesis
• Induces beta cell neogenesis, proliferation, differentiation
Adipose tissue
• Stimulates lipoprotein lipase
• Stimulates lipogenesis
• Increases fatty acid and glucose uptake
• Enhances insulin-dependent FAA incorporation
• Inhibits glucagon- and adrenergic receptor-stimulated lipolysis
CNS
• Induces proliferation of hippocampal progenitor cells
• Stimulates sensorimotor coordination
• Increases memory recognition
Toxicity Associated With Target
Effects in genetically modified mice. Knockout Mice—Single incretin (glucagon-like peptide-1, GLP-1) receptor knockout
mice as well as double incretin (both GIP and GLP-1) receptor knockout mice exhibited reduced body weight gain and
adipose tissue accretion after a 20-week high-fat diet. Over-expressing GLP-1 Transgenic Mice
Mice transgenically expressing a GLP-1 analog, exendin-4, exhibit comparatively similar glycemic responses (to wild-type
mice) following treatment with GLP-1 analogs. Body weight and basal food intake were not significantly different from
wild-type mice.
Dipeptidyl Peptidase-4 (DPP4) Inhibition Causes Elevated Level of GLP-1—Inhibition of DPP4 has been shown to
raise circulating active incretin levels (GIP and GLP-1). Apart from its glucose-dependent manner of stimulating insulin
secretion, GLP-1 (analogues and GIP) has been demonstrated to stimulate pancreatic beta-cell growth, differentiation,
proliferation and survival. Similarly, studies in both humans and in animal models have established DPP4 inhibition
results in an enhancement of glucose tolerance, insulin sensitivity and beta-cell glucose responsiveness.
Other Effects
Cardiovascular—Physiological changes in the levels of glucose, insulin, GLP-1 and ghrelin may influence the activity of the
heart and the blood pressure.
Adipocytes—Potential changes in fatty acid metabolism and increase in body fat.
Bone—Enhanced bone mass.
Gastrointestinal—Delayed gastric emptying.
Cancer—Pancreatic beta cell proliferation, hyperplasia and adenomas of thyroid C-cells.
Chapter 6: The Impact of Preclinical Planning and Study Outcome on the Risk Management of Biologicals
96
Appendix 6-1
Example and Case Study: Early Toxicology Assessment for a Hypothetical Novel Glucagon-like Peptide-1 Analog
Target Description/Indication/Mechanism
Molecule—Glucagon-like peptide-1 (GLP-1) is a single molecule, 30-amino acid peptide that binds with activity to either
GIP or GLP-1 receptors. It is secreted from gut endocrine L-cells in a glucose-dependent manner.
Pharmacology—GLP-1 is an incretin in normal physiology and a potent stimulant of insulin synthesis and release and beta
cell mass. It inhibits glucagon secretion, slows gastric emptying and has an anorectic effect. These actions lower blood
glucose in both normal subjects and in patients with type 2 diabetes.
Known Issue—The side effects of GLP-1 receptor agonists mimic the pharmacology of native GLP-1. Intravenous or
subcutaneous administration of GLP-1 causes nausea and vomiting in a dose-dependent manner the doses above which
GLP-1 causes GI side effects are higher than those needed to regulate blood glucose. May delay gastric emptying. May
alter PK of drugs that require rapid GI absorption. Hypoglycemia caused by GLP-1 agonists is rare
Target Population—Type 2 diabetics not reaching goal with current GLP-1 agonist therapies.
Target Distribution: Ubiquitously Expressed
Receptor location • Islets, stomach, small intestine, adipose tissue, adrenal cortex, lung, pituitary, heart, testis,
bone, and brain
Islets
• Stimulates glucose-induced insulin secretion
• Increase insulin gene transcription and biosynthesis
• Induces beta cell neogenesis, proliferation, differentiation
Adipose tissue
• Stimulates lipoprotein lipase
• Stimulates lipogenesis
• Increases fatty acid and glucose uptake
• Enhances insulin-dependent FAA incorporation
• Inhibits glucagon- and adrenergic receptor-stimulated lipolysis
CNS
• Induces proliferation of hippocampal progenitor cells
• Stimulates sensorimotor coordination
• Increases memory recognition
Toxicity Associated With Target
Effects in genetically modified mice. Knockout Mice—Single incretin (glucagon-like peptide-1, GLP-1) receptor knockout
mice as well as double incretin (both GIP and GLP-1) receptor knockout mice exhibited reduced body weight gain and
adipose tissue accretion after a 20-week high-fat diet. Over-expressing GLP-1 Transgenic Mice
Mice transgenically expressing a GLP-1 analog, exendin-4, exhibit comparatively similar glycemic responses (to wild-type
mice) following treatment with GLP-1 analogs. Body weight and basal food intake were not significantly different from
wild-type mice.
Dipeptidyl Peptidase-4 (DPP4) Inhibition Causes Elevated Level of GLP-1—Inhibition of DPP4 has been shown to
raise circulating active incretin levels (GIP and GLP-1). Apart from its glucose-dependent manner of stimulating insulin
secretion, GLP-1 (analogues and GIP) has been demonstrated to stimulate pancreatic beta-cell growth, differentiation,
proliferation and survival. Similarly, studies in both humans and in animal models have established DPP4 inhibition
results in an enhancement of glucose tolerance, insulin sensitivity and beta-cell glucose responsiveness.
Other Effects
Cardiovascular—Physiological changes in the levels of glucose, insulin, GLP-1 and ghrelin may influence the activity of the
heart and the blood pressure.
Adipocytes—Potential changes in fatty acid metabolism and increase in body fat.
Bone—Enhanced bone mass.
Gastrointestinal—Delayed gastric emptying.
Cancer—Pancreatic beta cell proliferation, hyperplasia and adenomas of thyroid C-cells.