OPERAT I NG REV I EW CON T I NU E D Optimum dose identified In the Phelan-McDermid syndrome model, the effect of four escalating dose levels was investigated. The results of this dose ranging study are shown in the charts below. They were consistent across all 8 behavioral tests and the incidence of seizures, demonstrating that the second highest dose was the optimum dose level in the mouse model. Comparison with human pharmacokinetic data from the Phase 1 clinical trial has informed the equivalent human dose for the Phase 2 trials in patients. A further observation was that the optimum dose in this 6-week study showed better efficacy than the same dose in an earlier study for 3 weeks, indicating that efficacy increases with treatment duration. In the Phase 2 trials Neuren is testing treatment with NNZ-2591 for 13 weeks. OPTIMUM DOSE IN MOUSE MODEL OF PHELANMCDERMID 9 Memory Learning Sociability WT + vehicle KO + vehicle KO + x mg/kg KO + 2x mg/kg KO + 4x mg/kg KO + 8x mg/kg 0% 60% 50% 30% 10% 10% Incidence of seizures OPTIMUM DOSE IN MOUSE MODEL OF PHELANMCDERMID 10 Motor function Anxiety Repetitive behavior Daily living Daily living PTIMUM DOSE IN M USE MODEL OF PHELANMCDERMID 10 Motor function Anxiety Repetitive behavior Daily living Daily living E IN MOUSE MODEL OF PHELAN9 Learning Sociability O + vehicle KO + x mg/kg KO + 2x mg/kg KO + 4x mg/kg KO + 8x mg/kg 60% 50% 30% 10% 10% Incidence of seizures OPTIMUM DOSE IN MOUSE MODEL OF PHELANMCDERMID 10 Motor function Anxiety Repetitive behavior Daily living Daily living OPTIMUM DOSE IN MOUSE MODEL OF PHELANMCDERMID 10 Motor function Anxiety Repetitive behavior Daily living Daily living OPTIMUM DOSE IN MOUSE MODEL OF PHELA MCDERMID Memory Learning WT + vehicle KO + vehicle KO + x mg/kg KO + 2x mg/kg KO + 4x mg/kg K 0% 60% 50% 30% 10% Incidence of seizures WT + vehicle KO + vehicle KO + x mg/kg 0% 60% 50% KO + 2x mg/kg KO + 4x mg/kg KO + 8x mg/kg 30% 10% 10% Neuren Pharmaceuticals Limited Annual Repor t 2022 12
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