ZGN-1061, a Novel MetAP2 Inhibitor, and Liraglutide Combine to Improve Glycemic Control and Reduce Body Weight in a Rat Model of Diet-Induced Obesity

Abstract

ZGN-1061 (1061) is a methionine aminopeptidase 2 (MetAP2) inhibitor being developed to improve glycemic control in T2D. This study investigated 5 weeks (weeks) of once-daily SC treatment with a submaximal 0.3 mg/kg dose of 1061, a maximal 0.4 mg/kg dose of liraglutide (lira), 1061+lira, or vehicle (N=10/group) on body weight (BW), food intake/preference, and glycemic control in the Gubra diet-induced obese (DIO) rat model (ad libitum fed chow and highly palatable high-fat, high-sugar [HFHS] diet). Fasting (4 hour) blood glucose (FBG) was collected weekly and a semifasted (16 hour access to 50% of daily energy requirement) OGTT was performed at week 4. At week 5 (day 33), BW changed by +1.7% with vehicle vs. -6.0% with 1061, -9.1% with lira, and -16.9% with 1061+lira (all p<0.001). BW loss occurred earlier with lira (day 1) than 1061 (day 5). Starting at day 6, intake of the HFHS diet was modestly reduced (15-30%) with 1061 vs. vehicle. In contrast, lira and 1061+lira induced rapid and sustained 40-50% and 50-80% reductions in intake of the HFHS diet, respectively, over the first 8-9 days. Cumulative (day 0-35) HFHS diet intake was reduced vs. vehicle by 1061 (13.4%, p=0.07), lira (17.8%, p<0.01), and 1061+lira (38.2%, p<0.001). Cumulative chow intake was increased by 1061 and 1061+lira but not lira alone. There was a modest reduction in FBG (mean week 1-5) with 1061 vs. vehicle (p=0.08), a significant reduction with lira, and 1061+lira produced the largest reduction (both p<0.001) that was significantly lower than either agent alone (both p<0.01). In the OGTT, 1061 reduced the glucose AUC vs. vehicle by 37% (p=0.07), lira by 60% (p<0.001), and 1061+lira by 80% (p<0.001), achieving an AUC that was no different from lean rats. In this DIO rat model, 1061 and lira had complementary effects on reducing BW and normalizing glycemic control. Combination treatment with 1061 and liraglutide may yield greater weight loss and glycemic control than either agent alone in patients with T2D. Disclosure B.F. Burkey: Employee; Self; Zafgen. P.J. Pedersen: None. T.X. Pedersen: Employee; Self; Gubra. M. Feigh: None. J. Vath: Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen. T.E. Hughes: Board Member; Self; Zafgen. Employee; Self; Zafgen. Stock/Shareholder; Self; Zafgen.