Risk Management Principles for Devices and Pharmaceuticals
97
Reproductive—Glucose regulation important for organogenesis and development.
Literature References (Abridged)
• Elahi D, et al. The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like pep-
tide-1 (7-37) in normal and diabetic subjects. Regul Pept. 1994 51:63-74.
• Gelling RW, et al. Lower blood glucose, hyperglucagonemia, and pancreatic cell hyperplasia in glucagon receptor
knockout mice. PNAS. 2003 100:1438-1443.
• Powers AC, D’Alessio D. Endocrine pancreas and pharmacotherapy of diabetes mellitus and hypoglycemia. In
Goodman and Gliman the Pharmacological Basis of Therapeutics (12th ed). 2011 (ed. Bruntion L, Chabner B, Knollman
B) McGraw Hill, NY. Chapter 43. 1237-1273.
• Hansotia T, et al. GIP and GLP-1 as incretin hormones: Lessons from single and double incretin receptor knockout
mice. Regul Pept. 2005 128:125-134.
• Russell-Jones D. The safety and tolerability of GLP-1 receptor agonists in the treatment of type-2 diabetes. 2010. Int J
Clin Pract. 64:1402-1414.
Previous Experience
Extensive literature reports on the clinical use of GLPs including with Exenatide, Exendin-4 and liraglutide
Early Toxicity Liabilities Assessment Summary
There is extensive preclinical and clinical information on safety signals for GLP-1, with nausea and weight loss being the
most significant effects. The literature suggests that any side effects associated with this activity should be manageable
and associated with glucose dynamics and fat metabolism.
Recommendations
Although information to date indicates that the side effects for GLP-1 are relatively mild, it must be kept in mind that
the candidate GLP-1 co-agonist molecule is a novel protein that has the potential for unexpected pharmacology and/or
toxicology profile. Therefore, although this molecule qualifies as a protein candidate, it would be appropriate for this pro-
gram to plan for pilot toxicology studies to provide guidance for species and dose selection for IND enabling toxicology
studies.
Timeline for Addressing Risks—Pre-Lead, Pilot Toxicity Studies, GLP Toxicity Studies, and in Clinic
Reproductive—Based on the target mechanism, it is likely that reproductive and developmental toxicity will be observed.
This risk should be characterized appropriately during the development of a clinical candidate (i.e., during Phase 2 or
beyond).
Autoimmunity/Immunogenicity—This should be characterized appropriately during preclinical development stages and
all clinical trial phases. There will be a need to determine the potential for anti-drug antibodies that cross-react with their
endogenous counterparts such as glucagon (i.e., autoimmunity). Immunogenicity assays should be in place prior to the
start of preclinical safety studies.
Risks to Candidate Development—Low, Medium, High
Developmental /Reproductive Risk: Medium—see above Other Effects
Cancer Risk: Medium—see above Other Effects
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Reproductive—Glucose regulation important for organogenesis and development.
Literature References (Abridged)
• Elahi D, et al. The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like pep-
tide-1 (7-37) in normal and diabetic subjects. Regul Pept. 1994 51:63-74.
• Gelling RW, et al. Lower blood glucose, hyperglucagonemia, and pancreatic cell hyperplasia in glucagon receptor
knockout mice. PNAS. 2003 100:1438-1443.
• Powers AC, D’Alessio D. Endocrine pancreas and pharmacotherapy of diabetes mellitus and hypoglycemia. In
Goodman and Gliman the Pharmacological Basis of Therapeutics (12th ed). 2011 (ed. Bruntion L, Chabner B, Knollman
B) McGraw Hill, NY. Chapter 43. 1237-1273.
• Hansotia T, et al. GIP and GLP-1 as incretin hormones: Lessons from single and double incretin receptor knockout
mice. Regul Pept. 2005 128:125-134.
• Russell-Jones D. The safety and tolerability of GLP-1 receptor agonists in the treatment of type-2 diabetes. 2010. Int J
Clin Pract. 64:1402-1414.
Previous Experience
Extensive literature reports on the clinical use of GLPs including with Exenatide, Exendin-4 and liraglutide
Early Toxicity Liabilities Assessment Summary
There is extensive preclinical and clinical information on safety signals for GLP-1, with nausea and weight loss being the
most significant effects. The literature suggests that any side effects associated with this activity should be manageable
and associated with glucose dynamics and fat metabolism.
Recommendations
Although information to date indicates that the side effects for GLP-1 are relatively mild, it must be kept in mind that
the candidate GLP-1 co-agonist molecule is a novel protein that has the potential for unexpected pharmacology and/or
toxicology profile. Therefore, although this molecule qualifies as a protein candidate, it would be appropriate for this pro-
gram to plan for pilot toxicology studies to provide guidance for species and dose selection for IND enabling toxicology
studies.
Timeline for Addressing Risks—Pre-Lead, Pilot Toxicity Studies, GLP Toxicity Studies, and in Clinic
Reproductive—Based on the target mechanism, it is likely that reproductive and developmental toxicity will be observed.
This risk should be characterized appropriately during the development of a clinical candidate (i.e., during Phase 2 or
beyond).
Autoimmunity/Immunogenicity—This should be characterized appropriately during preclinical development stages and
all clinical trial phases. There will be a need to determine the potential for anti-drug antibodies that cross-react with their
endogenous counterparts such as glucagon (i.e., autoimmunity). Immunogenicity assays should be in place prior to the
start of preclinical safety studies.
Risks to Candidate Development—Low, Medium, High
Developmental /Reproductive Risk: Medium—see above Other Effects
Cancer Risk: Medium—see above Other Effects