OPERATING REVIEW by both major types of brain cells – neurons and glia. IGF-1 in the brain is critical both for normal development and to maintain or restore the biological balance required for normal functioning. During development, the brain and the cells that comprise it change rapidly and in complex ways. IGF-1 and its metabolites play a significant role in regulating these changes. In the mature brain, these molecules play an important role in responding to disease, stress and injury. Trofinetide and NNZ-2591 mimic the function of the natural molecules in the brain, however each drug is designed to have a longer half-life in circulation, be suitable for use as an oral medication, more readily cross the blood brain barrier and have better stability for longer and easier storage and shipping. Whereas many drugs typically exert a specific effect on a specific target related to one symptom, trofinetide and NNZ-2591 exert diverse effects which can help to control or normalise abnormal biological processes in the brain. This means that the target is to have a broad impact on the condition rather than aiming to treat one symptom. NEUREN’S GROUND-BREAKING THERAPIES Neuren develops drug therapies for serious neurological conditions, caused by genetic abnormalities or brain injury, that have no or limited approved treatment options. These conditions involve disruptions to brain development or function which lead to a wide range of serious issues affecting nearly every aspect of life. The impact on the patients and their families is severe and life-long. Neuren strives to develop therapies in close collaboration with the leading specialist physicians and the well-organised patient advocacy organisations. Each condition is caused by a different genetic mutation, or in the case of hypoxic-ischemic encephalopathy (HIE) by brain injury resulting from lack of oxygen or blood flow to the brain at birth, but they share similar symptoms and the common characteristic of impaired connections and signalling between brain cells. Neuren’s two novel patented drugs, trofinetide and NNZ-2591 (ercanetide), potentially have broad utility in the treatment of neurological conditions. Both drugs are synthetic analogues of important molecules that occur naturally in the brain and are involved in the biology of IGF-1, a growth factor stimulated by growth hormone. In the central nervous system, IGF-1 is produced 3 Impaired communication between neurons, abnormal formation/pruning of dendrites & chronic inflammation Rett (MECP2) Fragile X (FMR1) Phelan-McDermid (SHANK3) Pitt Hopkins (TCF4) Angelman (UBE3A) | Prader-Willi (15q11-q13) | SYNGAP1-related disorder (SYNGAP1) Neurodevelopmental disorders Hypoxic-Ischemic Encephalopathy (lack of oxygen or blood flow to the brain before, during or shortly after birth) Brain injury Walking and balance issues Anxiety and hyperactivity Seizures Impaired communication Intellectual disability Impaired social interaction Developmental delays Cognitive impairment Seizures Cerebral palsy Impaired hand use Sleep disturbance Gastrointestinal problems Severe impact on nearly every aspect of life Long-term impact on survivors Excitotoxicity, mitochondrial dysfunction, and acute & chronic inflammatory processes Neuren’s drugs target the critical role of IGF-1 in this upstream process, using analogs of naturally occurring peptides that can be taken orally as liquids INTRODUCTION GROUND-BREAKING IMPACT ON PEDIATRIC NEUROLOGICAL ORPHAN INDICATIONS Impaired communication between neurons, abnormal formation/pruning of dendrites & chronic inflammation Excitotoxicity, mitochondrial dysfunction, and acute & chronic inflammatory processes Severe impact on nearly every aspect of life Walking and balance issues Anxiety and hyperactivity Seizures Impaired communication Intellectual disability Impaired social interaction Impaired hand use Sleep disturbance Gastrointestinal problems Neurodevelopmental disorders Long-term impact on survivors Development delays Seizures Cognitive impairment Cerebral palsy Brain injury Neuren’s drugs target the critical role of IGF-1 in this upstream process, using analogs of naturally occurring peptides that can be taken orally as liquids Neuren Pharmaceuticals Limited Annual Report 2025 4
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