NV-5138 for Treatment-Resistant Depression

Treatment-resistant depression (TRD) is a subset of major depressive disorder (MDD) that does not respond to appropriate courses of at least two currently marketed antidepressants. Traditional antidepressant therapies such as SSRIs and SNRIs are only modestly effective and have a very slow onset typically taking 8-12 weeks to show efficacy. Newer drugs that antagonize or otherwise modulate the presynaptic glutamate N-methyl-D-aspartic acid (NMDA) receptor, have demonstrated the potential for improved efficacy with a rapid onset of antidepressant effects (days as opposed to weeks) and today there are several NMDA modulators in clinical development for depression, including ketamine and related agents. Unfortunately, presynaptic NMDA receptor antagonism can cause significant side effects including dissociation (hallucination) and has abuse potential.

Since the initial observations connecting NMDA receptor modulation and depression, scientists have elucidated the mechanism that underlies the therapeutic antidepressant benefit seen with these agents, including increased production of key synaptic signaling proteins and increased number and function of new synapses (synaptogenesis). This new research has also clearly demonstrated that presynaptic NMDA receptor modulation with agents like ketamine activates mTORC1 signaling in postsynaptic neurons, which is required to initiate the cellular processes leading to the synaptogenesis and antidepressant effects of these agents.

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. Navitor is actively working to advance NV-5138 into clinical studies in the first half of 2018.

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