OPERATING REVIEW CONTINUED Preparation for the first ever Phelan-McDermid syndrome Phase 3 program During 2024, at a Type B End of Phase 2 Meeting, Neuren achieved alignment with the FDA on key features of the Phase 3 clinical trial program for PMS. A single pivotal Phase 3 trial will be a randomised, double-blind, placebocontrolled trial of treatment for 13 weeks in children aged 3 to 12 years with PMS. Participants may continue into an open-label extension study continuing treatment until commercial launch. There will be one active treatment group versus placebo, with a target dose equivalent to the dose tested in the Phase 2 trial. Based on the safety data from the Phase 2 clinical trial, Neuren proposed a less burdensome safety monitoring plan for the Phase 3 and open label extension trials, which was considered reasonable by the FDA, subject to review of the final protocol. This study will be the first ever pivotal clinical trial in PMS, which means there is no precedent for efficacy assessment. This will be the subject of a further Type C Meeting with the FDA, scheduled in early April 2025, to seek alignment on the primary efficacy endpoints in the Phase 3 clinical trial. In parallel with the FDA interaction, Neuren is continuing the extensive preparations for the trial, planning for mid-2025 commencement. 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. 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. Other indications Neuren recently announced the initiation of development of NNZ-2591 to treat 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. About two to three in every 1,000 births in high income countries and 10-30 per 1,000 births in low- and middle-income countries will be affected by HIE, which means that many thousands of babies and children experience HIE every year. It is one of the leading causes of neonatal death and neurodevelopmental disability worldwide. Neuren believes that 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. Neuren anticipates that NNZ-2591 in HIE will qualify for Orphan Drug and Rare Pediatric disease designations from the FDA. Leveraging the platform of clinical, non-clinical and manufacturing data that Neuren has built for NNZ-2591, a pre-IND meeting with the FDA is targeted in Q4 2025 before initiating a clinical trial in HIE patients. 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. 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 2024 10
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