Congress reauthorised the Rare Pediatric Disease PRV program to 30 September 2029. This means that marketing approval by FDA of NNZ-2591 in PMS would qualify Neuren for a PRV, of which Neuren would retain 100% ownership and proceeds of any sale. Strong foundations built for NNZ-2591 Neuren has meticulously built strong foundations to enable late-stage clinical development of NNZ-2591: Clear and consistent efficacy in mouse models Studies in a shank3 mouse model compared normal mice (“wild type”) and mice with a disrupted gene (“knockout”). The knockout mice exhibit behavioural and biochemical deficits that mimic PMS in humans. The wild type mice and the knockout mice were each treated with placebo and NNZ2591. Treatment with NNZ-2591 for 6 weeks eliminated all the deficits so that the knockout mice were indistinguishable from the wild type mice. Treatment had no impact on the wild type mice which is important from a safety point of view. Blood-brain barrier penetration confirmed As well as very high oral bioavailability, good penetration of the blood-brain barrier by NNZ-2591 has been demonstrated in a rodent study. A single dose was administered at 2 dose levels, with the high dose twice the low dose. The concentration of NNZ-2591 in the blood and cerebrospinal fluid was determined after 1.5 hours and again after 4 hours. The amount in the brain tissue was also measured after 4 hours. In each case the concentration was approximately proportional to the dose and after 4 hours the concentration in blood and brain tissue was approximately equivalent. Large scale manufacturing process developed Neuren has successfully developed a proprietary process for manufacturing drug substance at large scale with exceptional purity and high yield. Positive Phase 1 and Phase 2 clinical trial results Neuren completed a Phase 1 clinical trial, in which twice daily oral dosing of NNZ-2591 for seven days was safe and well tolerated in healthy volunteers at doses expected to be within the effective therapeutic range. In an open label Phase 2 trial in PMS patients aged 3 to 12 years at four hospitals in the US, which examined safety, tolerability, pharmacokinetics and efficacy over 13 weeks of treatment with NNZ-2591, significant improvement was assessed by both clinicians and caregivers across multiple efficacy measures. Improvements were consistently seen across clinically important aspects of PMS, including communication, behaviour, cognition/learning and socialisation. OPERATING REVIEW CONTINUED Phelan-McDermid syndrome has an overwhelming unmet medical need PMS is caused by a deletion or other change in the 22q13 region of chromosome 22, which includes the SHANK3 gene, or a mutation of the gene. PMS is also known as 22q13 deletion syndrome. The SHANK3 gene codes for the shank3 protein, which supports the structure of synapses between nerve cells in the brain. PMS has severe quality of life impacts for those living with the syndrome, as well as parents and siblings. There are no approved treatments for PMS despite its severely debilitating impact. The estimated prevalence of PMS is 1% of people diagnosed with autism, or between 1 in 8,000 and 1 in 15,000 males and females.1 It has historically been underdiagnosed, but this is changing with rising awareness and enhancement of genetic testing technologies. In November 2022, an important Externally-Led Patient Focused Drug Development (ELPFDD) Meeting was held, in order for the FDA and other key stakeholders to hear directly from patients, their families, caregivers, and patient advocates about the impact PMS has on patients’ daily lives. The meeting content was collated in a “Voice of the Patient” report. In 2023 for the first time an International Classification of Disease (ICD) code was assigned to PMS. In October 2025 Neuren was granted Fast Track designation by the FDA for the PMS program. Neuren currently holds Rare Pediatric Disease designation for NNZ-2591 in PMS. In February 2026 the United States 1 Phelan McDermid Syndrome Foundation (PMSF) (www.pmsf.org) FROM THE PHELAN-MCDERMID SYNDROME VOICE OF THE PATIENT REPORT: “ PMS has an overwhelming unmet medical need. There are no FDA approved treatments for PMS despite its severely debilitating manifestations. Parents and caregivers are open to trying almost anything to try to relieve their child’s suffering; most have tried an incredibly high number of treatments and approaches for symptom management, with very little success. Some received medications that caused more harm than good.” “ PMS has severe quality of life impacts on those living with the disease, as well as on parents and siblings. Most activities of daily life, including communicating needs or wants, self-care (bathing, dressing, toileting) and socializing with peers/ siblings are affected. Most individuals living with PMS rely on their parents and caregivers for all their daily needs, and many require 24-hour care.” Neuren Pharmaceuticals Limited Annual Report 2025 14
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