HYPOXIC ISCHEMIC ENCEPHALOPATHY (HIE) During 2025 Neuren initiated the development of NNZ-2591 for hypoxic-ischemic encephalopathy (HIE), a devastating type of brain injury caused when a baby’s brain does not receive enough oxygen or blood flow before or shortly after birth. Many thousands of babies and children experience HIE every year with estimated incidence rate of 2-3 in every 1,000 full-term births in high income countries and 10-30 per 1,000 live births in low and middle income countries.3 It is one of the leading causes of neonatal death and neurodevelopmental disability worldwide. Neuren believes NNZ-2591 can potentially provide a highly differentiated form of treatment continuing beyond acute treatment in the neonatal intensive care unit to target both the acute effects and chronic impairments resulting from HIE. In September 2025 Neuren commenced a formal partnership with Hope for HIE supporting development of NNZ-2591 to treat HIE. Hope for HIE is the global organisation connecting families, researchers, clinicians, biotech and more to improve the quality of life for children and families impacted by HIE. In February 2026 Neuren received feedback on its plan to submit an IND application for the treatment of HIE and the proposed initial clinical study of the pharmacokinetics, tolerability and safety of NNZ-2591 for one month in neonates and infants with HIE to open the IND. FDA generally accepted this IND-opening clinical study and the doses of NNZ-2591 to be evaluated, providing some guidance on the inclusion/exclusion criteria and safety monitoring. FDA requested that Neuren provides additional juvenile animal study data to support NNZ-2591 dosing in neonatal participants prior to initiating the clinical study. Neuren plans to generate this data before submitting the IND application and commencing the clinical study. In parallel Neuren is continuing to advance the logistical requirements for study execution. FDA also encouraged Neuren to submit a future meeting request to discuss appropriate endpoints, study population and safety monitoring for a subsequent study, which Neuren intends will support registration. OTHER POTENTIAL INDICATIONS The mechanism of action of NNZ-2591 is relevant for many other neurological conditions. Neuren previously announced positive top-line results from the Phase 2 clinical trial of NNZ-2591 in children with Angelman syndrome (AS). After treatment for 13 weeks, 11 out of 13 children showed improvement assessed by clinicians, with improvements seen in clinically important aspects of AS. In the 3-12 years age group all 8 children showed improvement. In 2025 Neuren added SYNGAP1-related disorder (SRD) into its neurodevelopmental disorders pipeline for NNZ-2591. SRD is caused by a variant on the SYNGAP1 gene located on Chromosome 6, which is responsible for producing the SYNGAP1 protein. The protein acts as a regulator in the synapses and insufficient production leads to impaired communication between neurons. This results in the many neurological issues seen in SRD patients including intellectual disability, low muscle tone, global development delay, epilepsy, sensory processing disorder, gross and fine motor skill delays, coordination disorder, speech delay, sleep and behavior disorder and autism spectrum disorder. In an in-vitro model of SRD in human iPSC-derived neurons, treatment with NNZ-2591 reversed the neuronal dysfunction caused by SYNGAP1 haploinsufficiency. As part of the expanded global partnership with Acadia signed in July 2023, Neuren granted Acadia exclusive worldwide licence for NNZ-2591 solely in Rett syndrome and Fragile X syndrome, which enabled coordinated global development and removed restrictions on Neuren for NNZ2591 in those two indications. Neuren retains worldwide rights to NNZ-2591 in all other indications. Potential future payments to Neuren related to NNZ-2591 in Rett syndrome and Fragile X syndrome are identical to the payments for trofinetide in each of North America and outside North America. Acadia is responsible for all costs of development and commercialization in those two indications. OPERATING REVIEW CONTINUED 3 Hope for HIE (Hope for HIE - Hypoxic Ischemic Encephalopathy) Neuren Pharmaceuticals Limited Annual Report 2025 17
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