755-P: A 26-Week Carcinogenicity Study with the Novel Glucagon Analog Dasiglucagon in CByB6F1-Tg(HRAS)2Jic Mice

Abstract

Carcinogenicity testing is a regulatory requirement for new pharmaceuticals indicated for chronic diseases. Historically, carcinogenicity testing has been done in 2-year “lifelong” studies in rats and mice. The challenges with these studies in terms of a high false-positive rate and a high background tumor incidence in control animals have led to the development of an alternative transgenic mouse model. The rasH2 mouse is a hemizygous transgenic mouse carrying the human c-Ha-ras gene with its own promoter/enhancer elements, which induces high enhancer activity. The advantages offered by rasH2 mice are the low rate of spontaneous background findings and a lower false-positive rate with a comparable ability to predict known human carcinogens as the 2-year bioassays. We undertook the current carcinogenicity study to assess the novel glucagon analog, dasiglucagon, in the rasH2 mouse model. Four groups of 25 male and female CByB6F1-g(HRAS)2Jic mice received once-daily subcutaneous administration of the vehicle (25 mM sodium phosphate buffer, 17 mg/mL propylene glycol, pH 6.5) or dasiglucagon at 1, 5, and 20 mg/kg. The high dose was selected to result in exposure at least 25 times higher than the relevant clinical exposure. A positive control group received a single intraperitoneal injection of N-methyl-N-nitrosourea. Dasiglucagon at doses up to 20 mg/kg/day to transgenic CByB6F1-Tg(HRAS)2Jic mice for 26 weeks did not result in any neoplastic changes to demonstrate that dasiglucagon was not carcinogenic in the transgenic CByB6F1-Tg(HRAS)2Jic mouse model. Neoplastic findings in stomach of positive control animals demonstrated the functionality of the transgene and the suitability of the batch of transgenic animals. The data provide additional confidence that dasiglucagon has an acceptable profile for use in the treatment of humans. Disclosure M. Elander: None. A. Froud: None.