Ann: J.P. Morgan Healthcare Conference recap, page-21

Given NNZ-2591’s mechanism of action—modulating insulin-like growth factor 1 (IGF-1) activity, reducing neuroinflammation, promoting synaptic function, and addressing neurodevelopmental impairments—Neuren Pharmaceuticals could target a range of conditions where these pathways play a central role. Here are some potential conditions the company could investigate:

1. Rare Neurodevelopmental Disorders

These conditions often have no approved treatments and share characteristics of synaptic dysfunction, neuroinflammation, and impaired IGF-1 signaling:

•Fragile X Syndrome:

•A leading inherited cause of intellectual disability and autism, involving disrupted synaptic plasticity.

•Preclinical data suggest IGF-1 modulation improves synaptic connectivity in this disorder.

•Tuberous Sclerosis Complex (TSC):

•A genetic disorder causing benign brain tumors and developmental delays.

•IGF-1 signaling is dysregulated in TSC, and targeting this pathway may improve outcomes.

•Cerebral Palsy (CP):

•A group of disorders affecting movement and development, often due to perinatal brain injury.

•IGF-1’s neuroprotective properties could support recovery and repair mechanisms.

•Rett Syndrome (Expanded Use):

•NNZ-2591 could complement Trofinetide to address Rett syndrome in broader populations or at later stages of disease.

2. Autism Spectrum Disorder (ASD) and Related Conditions

•Subgroups of ASD, particularly those with:

•Known genetic mutations (e.g., SHANK3 mutations in Phelan-McDermid syndrome).

•Evidence of neuroinflammation or synaptic dysfunction.

•NNZ-2591 could be explored to target behavioral and cognitive impairments linked to these mechanisms.

3. Neurodegenerative Diseases

These conditions involve synaptic loss, neuroinflammation, and oxidative stress—areas where NNZ-2591 may have therapeutic potential:

•Alzheimer’s Disease:

•IGF-1 levels decline with age, contributing to neurodegeneration and cognitive impairment.

•NNZ-2591 could target synaptic dysfunction and neuroinflammation in early or mild Alzheimer’s.

•Amyotrophic Lateral Sclerosis (ALS):

•Impaired IGF-1 signaling is implicated in motor neuron degeneration.

•Modulating IGF-1 activity may protect motor neurons and slow disease progression.

•Parkinson’s Disease:

•IGF-1 may reduce neuroinflammation and support dopaminergic neurons affected in Parkinson’s.

4. Traumatic and Acquired Brain Injuries

•Traumatic Brain Injury (TBI):

•IGF-1 is critical for neuronal repair and recovery following injury.

•NNZ-2591 could improve cognitive and functional outcomes by reducing neuroinflammation and promoting neurogenesis.

•Hypoxic-Ischemic Encephalopathy (HIE):

•Often seen in newborns with oxygen deprivation, HIE involves neuroinflammation and cell death, where IGF-1 modulation could be neuroprotective.

5. Metabolic and Endocrine Disorders Affecting the Brain

•Chronic Kidney Disease (CKD) and Cognitive Impairment:

•CKD reduces IGF-1 levels, contributing to cognitive decline and brain atrophy.

•NNZ-2591 could address these effects by restoring IGF-1 activity.

•Diabetes-Related Cognitive Decline:

•In Type 1 and Type 2 diabetes, IGF-1 dysregulation is linked to cognitive impairments.

•NNZ-2591 might protect against insulin resistance-related brain dysfunction.

6. Rare Genetic Syndromes

Many rare syndromes feature IGF-1 dysregulation or neurodevelopmental impairments, such as:

•Angelman Syndrome:

•A condition already under investigation by Neuren, where synaptic dysfunction and neuroinflammation play a role.

•Kabuki Syndrome:

•A rare condition with intellectual disability and growth issues, potentially linked to IGF-1 dysregulation.

•Noonan Syndrome:

•Involves short stature, learning disabilities, and cardiac issues, potentially benefiting from IGF-1 pathway modulation.

7. Muscle and Neuromuscular Disorders

•Duchenne Muscular Dystrophy (DMD):

•IGF-1 supports muscle regeneration and may mitigate the effects of progressive muscle loss.

•Sarcopenia:

•Age-related muscle loss linked to declining IGF-1 levels, where NNZ-2591 could enhance muscle strength and repair.

8. Epileptic Encephalopathies

•Dravet Syndrome or Lennox-Gastaut Syndrome:

•Severe epilepsy syndromes with comorbid cognitive and developmental impairments, where IGF-1 modulation may reduce neuroinflammation and improve function.

Why These Conditions?

•Mechanistic Fit: NNZ-2591 targets core pathways (IGF-1 signaling, neuroinflammation, synaptic function) relevant to these conditions.

•Market Opportunity: Many of these diseases have limited or no treatment options, aligning with Neuren’s focus on unmet needs.

•Rare Disease Focus: Rare diseases often have expedited regulatory pathways (e.g., orphan drug designation), making them attractive for drug development.

Prioritization Criteria:

Neuren could prioritize conditions based on:

1.Overlap with Known Mechanisms: Disorders with confirmed IGF-1 or neuroinflammation abnormalities.

2.Market Exclusivity: Rare diseases with no approved therapies.

3.Pipeline Synergies: Disorders that align with ongoing research on NNZ-2591.

Key Takeaway:

Neuren could expand NNZ-2591 research into conditions like Fragile X Syndrome, TBI, Alzheimer’s, and muscle disorders, while continuing its focus on rare pediatric syndromes to maximize the drug’s therapeutic and commercial potential.