Effects on biochemistry and brain cell structure confirmed Biochemical testing in the PMS model showed that the abnormal length of dendritic spines between brain cells, the excess activated ERK protein (pERK) and the depressed level of IGF-1 in the knockout mice were all normalised after treatment with NNZ-2591. PITT HOPKINS SYNDROME (PTHS) During 2025 Neuren was granted Fast Track designation by the FDA for the PTHS program and a new patent covering NNZ-2591 to treat PTHS was also granted by the US Patent and Trademark Office, with expected expiry in 2040. In early 2026 Neuren received feedback from the FDA regarding its clinical development plans for PTHS, which indicated that in a controlled trial to demonstrate efficacy of NNZ-2591 , a PTHS-specific clinical global impression (CGI) scale may be used as a co-primary endpoint if it is accompanied by an observer-reported functional outcome measure. This is similar to the approach that was agreed and is being implemented in Neuren’s ongoing Phase 3 trial in Phelan McDermid syndrome (PMS). Neuren is currently assessing alternative trial designs and endpoint analysis methodologies to accommodate that PTHS is significantly rarer and generally more profoundly disabling than PMS. Further interaction with the FDA will likely be required to finalise this assessment. Previously in 2024, Neuren announced positive top-line results from the Phase 2 clinical trial of NNZ-2591 in children with PTHS. After treatment for 13 weeks, 9 out of 11 children showed improvement assessed by clinicians and significant improvement was observed by both clinicians and caregivers in clinically important aspects of PTHS, including communication, social interaction, cognition and motor abilities. The estimated prevalence of PTHS is between 1 in 34,000 and 1 in 41,000 males and females.2 CORRECTING IMPAIRED SIGNALING IN NEURONS Correction of abnormal dendritic spines in mouse models: Left - Phelan-McDermid syndrome (shank3) Right - Fragile X syndrome (fmr1) Abnormal dendrites in shank3 knockout mice Correction in fmr1 knockout mice after treatment with trofinetide (NNZ-2566) Normalisation after treatment with NNZ-2591 OPERATING REVIEW CONTINUED 2 Pitt Hopkins Research Foundation (PHRF) (pitthopkins.org) Neuren Pharmaceuticals Limited Annual Report 2025 16
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