NV-5138 for Treatment-Resistant Depression

NV-5138, a first-in-class, orally active small molecule that selectively activates mTORC1 in the brain, has broad potential to treat neurological conditions such as depression, cognitive impairment and other indications that result from suppressed mTORC1 activity in the brain.

mTORC1 Activity is Suppressed in Depression

Depression is a Global Problem with Enormous Personal and Societal Impact

Major Depressive Disorder (MDD) affects over 16 million people in the US and more than 300 million people worldwide. It is the second leading cause of disability worldwide with over $200 billion in annual costs for healthcare, including $17 billion on anti-depressant therapies, and lost productivity in the US alone.

Traditional antidepressant therapies such as SSRIs and SNRIs are effective in only about half of treated patients and have a very slow onset, typically taking 8-12 weeks to show efficacy. In the US alone, over 3 million people suffering from Treatment-Resistant Depression (TRD) do not respond to courses of at least two antidepressants. TRD patients incur more than 35 lost work days annually (double the MDD rate) and have particularly poor prognoses for remission of their symptoms.

Rapid-Acting Anti-depressants Indirectly Activate mTORC1 in the Brain

Newer drugs including ketamine and related antidepressant agents that modulate the presynaptic N-methyl-D-aspartic-acid (NMDA) receptor have demonstrated the potential for improved efficacy with a rapid onset (days vs. weeks). Unfortunately, these agents indirectly activate mTORC1 signaling via presynaptic neurons, which can also cause significant neurological side effects including dissociation (hallucination) and has abuse potential.

NV-5138 Directly Activates mTORC1 in the Brain

NV-5138 is an orally active, brain penetrant small molecule leucine mimetic that directly activates mTORC1 by binding to Sestrin, a leucine amino acid sensor. Since NV-5138 works through direct, post-synaptic activation of the mTORC1 signaling pathway, it offers the potential for rapid-acting antidepressant benefits without the psychotomimetic side effects and abuse potential observed with many NMDA receptor targeted therapeutics. Preclinical models have demonstrated that NV-5138 produces rapid upregulation of key synaptic proteins, synaptic remodeling in the prefrontal cortex and hippocampus, sustained antidepressant behavioral responses, cognitive improvements and compound-specific spectral power changes, as measured by quantitative electroencephalography (qEEG).

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