Liraglutide Data & Cancer-FDA Briefing Report
Interesting read
1) In Rats, thyroid c-cell tumors occurred at all doses tested in males and females in a 104-week repeat subcutaneous dose study of 0.075, 0.25, or 0.75 mg/kg/day liraglutide in Sprague Dawley rats (Table 1), but survival was unaffected by treatment (See data in Table 1).
2) Focal c-cell hyperplasia, a preneoplastic lesion, increased above concurrent control groups and above the historical control group range at >0.075 mg/kg liraglutide in males and at >0.25 mg/kg in females.
3)In mice, C-cell hyperplasia dose dependently increased above concurrent controls and above the historical control group range at >0.2 mg/kg liraglutide in males and females. Based on historical control group data from CD-1 mice, ............
4) Applicant proposed a novel GLP-1 receptor-dependent mode of action, then performed mechanistic studies to evaluate it. The proposed mode of action is:
a) GLP-1 receptor agonists activate thyroid c-cell GLP-1 receptors.
b)C-cell GLP-1 receptor activation stimulates calcitonin secretion (calcitonin is a ‘prehyperplasia’ biomarker).
c)C-cell GLP-1 receptor activation increases calcitonin synthesis.
d)Persistent calcitonin secretion and increased calcitonin synthesis causes c-cell hyperplasia.
e)C-cell hyperplasia progresses to c-cell tumors, including progression of benign adenomas to carcinomas.
5) Liraglutide different from Exenatide because:
Liraglutide (NN2211 or NNC 90-1170) is a lipidated GLP-1 analog with prolonged
pharmacologic activity after subcutaneous administration (Figure 1). Its prolonged activity is due to delayed absorption resulting from self association of the attached lipid and because liraglutide is highly plasma protein bound in systemic circulation, it is resistant to inactivation by DPP-IV.
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