ICA6150349, a 38-amino-acid peptide, is a glucagon analog that is highly selective for the human glucagon receptor. In a 14-day toxicity study, rats and cynomolgus monkeys received ICA6150349 at doses of 0, 0.875, 8.75, 87.5 mcg/day and 0, 17.92, 179.2, 3584 mcg/day, respectively. Animals were evaluated for reversibility of findings for an additional 14 days. The TK characteristics of ICA6150349 were also determined. In rats, there was a pharmacologically expected dose-dependent decrease in body weight (BW) gains and food consumption, which demonstrated a recovery trend. Clinical pathology and anatomic pathological changes, largely restricted to the exaggerated pharmacological effect of glucagon at high exposures, had mostly recovered during the dose-free period. ICA6150349 exposures (AUC0-24) increased dose-proportionally in male and female rats on D2. On D14, exposure was 40-60% lower than on D2 in the 0.875 and 8.75 mcg/day dose groups and similar to D2 in the 87.5 mcg/day dose group after adjustment for changes in BW. ADAs were observed in rats from all dose groups, but did not impact the TK of ICA6150349. In cynomolgus monkeys, the effects of ICA6150349 were limited to minimally decreased RBC mass (hemoglobin, red blood cell count, and hematocrit) at 3584 mcg/day with recovery. ICA6150349 exposure (AUC0-24) increased dose-proportionally on D2. On Day 14, exposures were 14-65% lower than on D2 in all groups except the 3584 mcg/day females. ADA were observed in 46.7% of treated monkeys; however, ADA status only affected TK at the 3584 mcg/day dose level. Overall, ICA6150349 was well tolerated. Nonclinical safety studies identified no adverse effects (based on the minimal magnitude of change, severity grading and reversibility) at any dose level tested with a NOAEL of 87.5 mcg/day in rats and 3584 mcg/day in monkeys. All observed effects have been non-adverse, reversible, and consistent with known actions of glucagon.


D. Zane: None. R. Singh: None. J. Shelton: None. S. Roller: Employee; Self; Intarcia Therapeutics, Inc. M. Paulik: Employee; Self; Intarcia Therapeutics, Inc. J. Way: Employee; Self; Intarcia Therapeutics, Inc. W.C. Blackwell: Employee; Self; Intarcia Therapeutics, Inc. V. Srivastava: Employee; Self; Intarcia Therapeutics, Inc. R. Hodge: Employee; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc. P.L. Feldman: Employee; Self; Intarcia Therapeutics, Inc. T.R. Alessi: Employee; Self; Intarcia Therapeutics, Inc..

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