Navitor Pharmaceuticals, Inc., the leader in the development of mTORC1-targeted therapeutics designed to help patients live longer and healthier lives, announced today the publication of a peer-reviewed article in the Journal of Clinical Investigation, highlighting the rapid and long-lasting antidepressant effects of NV-5138 in behavioral models of depression and treatment response. NV-5138 is a first-in-class, orally-active small molecule that directly activates mTORC1, the gatekeeper of cellular metabolism and renewal, which is suppressed in the brain of people suffering from depression. NV-5138 is currently in Phase 1 development for the treatment of patients who have failed to respond to two or more typical antidepressants and are considered to have treatment-resistant depression (TRD). The results from the portion of the study evaluating efficacy in TRD patients is expected in mid-2019.
The results published today demonstrate that a single oral dose of NV-5138, Navitors unique mTORC1 activator, produces rapid antidepressant behavioral responses, with distinct changes in synaptic morphology observed during the same time frame. These synaptic and behavioral responses were similar in magnitude to ketamine but occur via an initial cellular mechanism that is completely independent of NMDA receptor modulation, said George P. Vlasuk, Ph.D., President and Chief Scientific Officer of Navitor.
In the study, the effects of NV-5138 were evaluated in standard experimental behavioral paradigms that are responsive to chronic administration of typical antidepressants, including tests of despair, anxiety and chronic unpredictable stress. The results demonstrate that a single oral dose of NV-5138 produced rapid and long-lasting antidepressant efficacy in these settings. Additionally, NV-5138 was also observed to increase the number and function of dendritic spines indicating changes in synaptic morphology in neurons comprising the portion of the brain known to be involved in the maintenance of mood.
Ronald S. Duman, the Elizabeth Mears and House Jameson Professor of Psychiatry and Neuroscience, and Director of the Abraham Ribicoff Research Facility at the Yale School of Medicine, the lead author on the study, commented, The results also demonstrate that the antidepressant effects of NV-5138 require mTORC1 signaling, as well as biologically active brain derived neurotropic factor. Together these findings characterize a novel mechanism, direct activation of mTORC1 signaling via the upstream regulator sestrin, and are consistent with the requirement of post-synaptic activation of mTORC1, which has been established for other rapid antidepressant agents, including ketamine.
The article, titled Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation is published in the latest online edition of the Journal of Clinical Investigation, an open access journal published by the American Society for Clinical Investigation, focused on discoveries in basic science and clinical biomedical science that will advance the practice of medicine. The paper can be found at https://www.jci.org/articles/view/126859.
NV-5138 is an orally bioavailable small molecule that directly and transiently activates mTORC1, the master modulator of cellular metabolism, which is suppressed in the brain of patients suffering from depression. NV-5138 binds to and modulates sestrin, a recently discovered cellular sensor protein for the amino acid leucine, a potent natural activator of mTORC1. As opposed to many other organ systems like skeletal muscle, leucine is a poor activator of mTORC1 in the brain since it is principally used as a metabolic precursor for neurotransmitter and protein synthesis. NV-5138 was designed to avoid the metabolic fate of leucine in the brain and thus serves as an effective activator of mTORC1 in this tissue. Results from preclinical models demonstrate that oral administration of 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). Navitors strong intellectual property portfolio includes issued composition of matter patent protection for NV-5138 and related compounds.
mTORC1, or Complex 1 of the mechanistic target of rapamycin, activity governs the pace and ability of the cell to synthesize protein and other cellular components. Increased mTORC1 activity contributes to a broad array of diseases of aging by increasing protein misfolding and driving cellular stress, inflammation, and fibrosis. In other disease states such as severe depression, inadequate mTORC1 activity contributes to disease pathology by limiting energy utilization and protein synthesis, leading to impaired function. Multiple preclinical studies have shown that mTORC1 activation is required for the efficacy of many rapid-acting antidepressant compounds, including but not limited to modulators of the N-methyl-D-aspartic-acid (NMDA)-mediated signaling pathway like ketamine.1
Navitor Pharmaceuticals, Inc. is the leader in the development of mTORC1-targeted therapeutics designed to help patients live longer and healthier lives. The Companys proprietary platform enables specific modulation of mTORC1, the gatekeeper of cellular metabolism and renewal, with the first-ever absolutely selective mTORC1 inhibition and the unique ability for mTORC1 activation. Navitors lead clinical-stage candidate, NV-5138, is a small molecule that directly activates mTORC1 and is being developed for treatment-resistant depression, with additional opportunities in cognition and memory. The Companys NÎ›Valog program, which provides unprecedented selectivity in mTORC1 inhibition, is initially targeting chronic kidney disease and has broad potential application for age-related diseases. For more information, please visit www.navitorpharma.com.
1. Zanos, P. et al., CNS Drugs. 2018; 32(3): 197-227