NV-5138 for Treatment-Resistant 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. Depression is the 2nd leading cause of disability worldwide with over $200 billion in annual costs for healthcare 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. Nevertheless, over $17 billion is spent on (largely generic) antidepressants annually in the US.

Over 3 million MDD patients do not respond to appropriate courses of at least two currently marketed antidepressants; these Treatment-Resistant Depression (TRD) patients incur more than 35 lost work days annually, double the MDD rate, and have particularly poor prognoses for remission of their symptoms.

mTORC1 Activity is Suppressed in Depression

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

Newer drugs including ketamine and related antidepressant agents that modulate the presynaptic NMDA receptor have demonstrated the potential for improved efficacy with a rapid onset (days vs. weeks). These agents indirectly activate mTORC1 signaling in postsynaptic neurons, which is required to initiate the production of key synaptic signaling proteins, an increased number and function of new synapses (synaptogenesis) and thus the antidepressant effects of these agents. Unfortunately, indirect activation of mTORC1 via presynaptic NMDA receptor antagonism can also cause significant neurological side effects including dissociation (hallucination) and has abuse potential.

Navitor Lead Compound Directly Activates mTORC1 in the Brain

Navitor has developed NV-5138, an orally available small molecule that directly activates mTORC1 activity by binding and modulating Sestrin2, a leucine amino acid sensor. Results from preclinical models demonstrate that NV-5138 produces rapid upregulation of key synaptic signaling proteins, synaptogenesis and antidepressant behavioral responses via the direct activation of the mTORC1 signaling pathway. Since NV-5138 does not directly modulate NMDA receptor function, the compound may not have the side effects and abuse potential of the NMDA receptor modulators in development.

In June 2018 Navitor advanced NV-5138 into human Phase 1 clinical studies for the treatment of MDD/TRD.

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