Fig. 3.

Efficacy of AGI-026 in reversing the phenotype observed in Idh2R140Q mice. Treatment was administered twice daily for 13 weeks. (a) Inhibition of 2HG in plasma and heart following 6 weeks’ treatment with AGI-026 10 mg/kg compared with vehicle (n = 8 for plasma, n = 7 for heart Idh2wt-veh, and n = 5 for other groups). (b) Kaplan-Meier survival curves in Idh2R140Q mice treated with 10 mg/kg AGI-026 or vehicle and Idh2wt mice receiving vehicle. Statistical significance (p) tested using the log-rank (Mantel-Cox) test. (c) Histopathological analysis of heart tissue in Idh2wt mice and Idh2R140Q mice with and without AGI-026 treatment, showing rescue of cardiac hypertrophy (cytoplasmic and nuclear enlargement) with treatment (scale bar denotes 100 μm). (d) Inhibition of 2HG in plasma following 6 weeks’ treatment with AGI-026 compared with vehicle in the second efficacy study (n = 20 for Idh2wt-veh, n = 21 for Idh2R140Q-veh, n = 14 for Idh2R140Q-AGI 2 mg/kg, and n = 10 for Idh2R140Q-AGI 10 mg/kg); % inhibition calculated as 100 % in Idh2wt-veh and 0 % in Idh2R140Q-veh. (e) Kaplan-Meier survival curves in Idh2R140Q mice treated with 2 mg/kg AGI-026, 10 mg/kg AGI-026 or vehicle and Idh2wt mice receiving vehicle. Statistical significance (p) tested using the log-rank (Mantel-Cox) test. (f) Left ventricular mass/body weight ratio and (g) ejection fraction assessed by echocardiogram at week 13 (n = 20 for Idh2wt-veh, n = 16 for Idh2R140Q-veh, n = 13 for Idh2R140Q-AGI 2 mg/kg, and n = 9 for Idh2R140Q-AGI 10 mg/kg). Error bars represent mean ± standard deviation; statistical significance (p) was tested with one-way ANOVA with Sidak’s multiple comparison test