NNZ-2591 FOR MULTIPLE NEURODEVELOPMENTAL DISORDERS Neuren is developing NNZ-2591 for four other serious neurodevelopmental disorders that emerge in early childhood and have no or limited approved treatment options. The estimated number of potential patients being targeted across these four disorders is more than five times larger than Rett syndrome. Potential patients Disorder Gene mutation Published prevalence estimates US1 Europe1 RoW1, 2 Phelan-McDermid SHANK3 1/8,000 to 1/15,000 males and females 24,000 31,000 104,000 Pitt Hopkins TCF4 1/34,000 to 1/41,000 males and females 6,000 8,000 28,000 Angelman UBE3A 1/10,000 to 1/20,000 males and females 19,000 24,000 81,000 Prader-Willi 15q11-q13 1/10,000 to 1/30,000 males and females 17,000 21,000 72,000 66,000 84,000 285,000 1 Estimates derived by applying the mid-point of the prevalence estimate range to the populations under 60 years 2 RoW comprises Japan, China (urban population), Brazil, Israel, South Korea, Australia and New Zealand All four programs have been granted Orphan Drug designation by the US Food and Drug Administration (FDA) and are being developed under Investigational New Drug (IND) applications. In designing and executing the NNZ-2591 development program, Neuren has been able to leverage the extensive and highly relevant experience the management team has gained from the trofinetide Rett syndrome program across manufacturing, non-clinical, clinical and regulatory. Phase 2 clinical trials Phase 2 clinical trials are being conducted in all four indications. The open label trials are each enrolling up to 20 children to examine safety, tolerability, pharmacokinetics and efficacy over 13 weeks of treatment with NNZ-2591. All subjects receive NNZ-2591 as an oral liquid dose daily, with escalation in two stages up to the target dose during the first 6 weeks of treatment, subject to independent review of safety and tolerability data. The study begins with 4 weeks of observation to thoroughly examine baseline characteristics prior to treatment, against which safety and efficacy are assessed for each child. This is followed by the treatment period of 13 weeks. A follow-up assessment is made 2 weeks after the end of treatment. The overall aim of these first trials is to expedite the generation of data that will enable the subsequent trials to be designed as registration trials. In 2023 positive results were achieved in the Phelan-McDermid syndrome trial and enrolment was completed in both the Pitt Hopkins and Angelman syndrome trials. Top-line results are anticipated for Pitt Hopkins in Q2 2024 and for Angelman in Q3 2024. OPERATING REVIEW CONTINUED Phelan-McDermid Pitt Hopkins Angelman Prader-Willi n subjects Up to 20 Up to 20 Up to 20 Up to 20 Age range 3 to 12 3 to 17 3 to 17 4 to 12 Location US US Australia US Screening/Baseline Week 0 Week 4 Week 10 Week 17 Week 19 Up-titration to 12mg/kg BID NNZ-2591 treatment Follow-up Phase 3 preparation Non-clinical toxicity studies and optimisation of drug product and drug substance manufacturing Neuren Pharmaceuticals Limited Annual Report 2023 9
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