OPERATING REVIEW CONTINUED Phelan-McDermid syndrome has an overwhelming unmet medical need Phelan-McDermid syndrome (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 (EL-PFDD) 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. 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.” Strong foundations built for NNZ-2591 Neuren has meticulously built strong foundations to enable clinical development of NNZ-2591 in multiple indications. Clear and consistent efficacy in mouse models of all four disorders The studies in these models compared normal mice (“wild type”) and mice with a disrupted gene (“knockout”). The knockout mice exhibit behavioural and biochemical deficits that mimic each disorder in humans. The wild type mice and the knockout mice were each treated with placebo and NNZ-2591. In all four models, treatment with NNZ-2591 for 6 weeks eliminated all the deficits so that the knockout mice were indistinguishable from the wild type mice. In the Prader-Willi syndrome model, treatment with NNZ-2591 also normalized fat mass (obesity), insulin levels and IGF-1 levels. Treatment had no impact on the wild type mice which is important from a safety point of view. Following review of the data from the mouse models and the mechanistic rationale for treatment, FDA granted Orphan Drug designation for NNZ-2591 in each of the four disorders. Neuren Pharmaceuticals Limited Annual Report 2023 12
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