First data on NV-5138 demonstrating direct mTORC1 activation resulting in ketamine-like rapid antidepressant effects in preclinical animal models
Navitor unveils first therapeutic resulting from its mTORC1 drug development strategy targeting nutrient sensor proteins
CAMBRIDGE, Mass., November 15, 2017 – Navitor Pharmaceuticals, Inc., a biopharmaceutical company developing novel medicines that target the cellular nutrient signaling proteins regulating mTORC1 activation to treat serious diseases including neurological and fibrotic disorders, immunometabolism and certain rare diseases, announced today that its direct mTORC1 activator small molecule NV-5138, has been designated as the company’s lead drug candidate to be developed for treatment-resistant depression (TRD). This announcement coincides with the presentation of groundbreaking data for NV-5138 in preclinical studies, including several models of depressive-like behavior, being presented at the Society for Neuroscience’s 47th annual meeting, Neuroscience 2017, on November 11-15 in Washington, D.C.
With the announcement of NV-5138 as Navitor’s first drug program, the company is also revealing its drug development strategy of targeting nutrient sensor proteins, which enabled the identification of NV-5138, a small molecule targeting Sestrin2 to selectively modulate mTORC1 signaling in neurons to specifically intervene in the disease process underlying TRD. Navitor gained insight into the new biology of nutrient sensors based on cutting-edge discoveries by the company’s scientific founder, David M. Sabatini, MD, PhD, Professor of Biology at MIT, Member of the Whitehead Institute for Biomedical Research, and Investigator at Howard Hughes Medical Institute. Concurrently, Navitor leveraged preclinical observations that have shown mTORC1 activation as critical for the efficacy of rapid-acting modulators of the NMDA (N-methyl-D-aspartic acid)-mediated signaling pathway like ketamine, which is an active area of innovative drug development for depression.1,2
“We are pleased to announce Navitor’s first clinical candidate designed to selectively activate mTORC1 signaling by specifically targeting a nutrient sensor,” said George Vlasuk, PhD, President and Chief Executive Officer of Navitor. “We see the development of NV-5138 in TRD as a pioneering advance toward unlocking the therapeutic potential of modulating the mTOR signaling pathway to treat a wide range of human diseases.”
Navitor is reporting results for the first time on the preclinical efficacy of NV-5138 in TRD in a poster presentation at Neuroscience 2017 by Ronald S. Duman, PhD, Elizabeth Mears and House Jameson Professor of Psychiatry and Professor of Neuroscience at the Yale School of Medicine. Highlights of the collaborative findings include:
- NV-5138 demonstrated antidepressant effects in several well-established behavioral models of depressive behavior without affecting basal locomotor activity.
- The effects of NV-5138 were observed for up to 7 days following a single oral dose despite a short pharmacokinetic half-life and brain exposure of approximately 3 hours.
- Following oral administration, NV-5138 activated the mTORC1 pathway in the medial pre-frontal cortex (mPFC) of the brain similar to the NMDA-targeting agent, ketamine administered by injection.
- The pharmacological activity of NV-5138 was blocked by infusion of rapamycin into the mPFC prior to oral administration of the compound demonstrating that the effects of NV-5138 are mediated by mTORC1 activation; this was also previously demonstrated in multiple laboratories for ketamine.
- NV-5138 administration rapidly increased the levels of synaptic proteins in the mPFC, including GluA1 and synapsin1, as well as increased spine density and enhanced synaptic function of mPFC layer V pyramidal neurons.
“Our results show that NV-5138 produces behavioral responses and concomitant synaptic remodeling consistent with a rapid-acting antidepressant through the direct activation of the mTORC1 signaling pathway,” said Dr. Duman. “The data demonstrate the possibility that modulation of Sestrin2, a leucine amino acid sensor, is a novel target for development of rapid-acting antidepressants.”
“I am encouraged by the preclinical activity of NV-5138, and its potential as an oral treatment for TRD,” said Mauricio Fava, MD, Director of the Division of Clinical Research of the Massachusetts General Hospital (MGH) Research Institute and member of the Navitor Clinical Advisory Board. “It is our hope that patients suffering from TRD will benefit from these findings because of a number of rapidly acting antidepressants in clinical development, appearing to mediate their beneficial effects by activating mTORC1.”
About Rapid Acting Antidepressants and mTORC1 Activity
New antidepressant drugs that modulate the 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 at several NMDA modulators in clinical development for depression, including ketamine and related agents. 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 in specific pre-clinical settings, which increase production of key synaptic signaling proteins and increase the number and function of new synapses (synaptogenesis). This new research demonstrates that NMDA receptor modulation activates the mTORC1 signaling pathway, which is required to initiate the cellular processes like protein synthesis that lead to the synaptogenesis and antidepressant effects of these agents. Although the initial target engagement of these agents occurs within a short time frame of a few hours, this results in sustained, long-lasting synaptic and behavioral effects of days to even weeks after a single treatment.
NV-5138 is an orally bioavailable, 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 proteins, synaptogenesis and antidepressant behavioral responses via the direct activation of the mTORC1 signaling pathway. Since NV-5138 does not directly modulate the NMDA receptor pathway, the compound may not have the side effects and abuse potential of the NMDA receptor modulators currently in development. Navitor is actively working to advance NV-5138 into clinical studies in the first half of 2018.
About Nutrient Sensors for Modulating mTORC1 Activity
Nutrient sensors are specialized, intracellular proteins expressed in a cell to enable it to sense and respond to the availability of amino acids, glucose, and other biomolecules and direct normal cell function. In different tissues the availabilities of certain amino acids – the building blocks of proteins – initiate cellular processes by regulating mTORC1 activity to maintain homeostasis. The amino acid sensors Sestrin2 and CASTOR have been shown to direct mTORC1 activity based upon availabilities of the amino acids leucine and arginine, respectively. These findings provide a mechanism to unlock the therapeutic potential of mTOR and restore normal mTORC1 activity to treat diseases caused by dysfunctional mTORC1 activity.
Navitor Pharmaceuticals, Inc., is a biopharmaceutical company discovering and developing novel medicines that target the nutrient sensing pathways that regulate mTORC1, a master regulator of cellular growth and metabolism. The company’s proprietary drug discovery platform unlocks the therapeutic potential of mTOR by bringing together deep knowledge into nutrient sensors, proprietary biological tools and expertise regarding the correlation of mTORC1 activity in disease. Navitor’s small molecule therapeutics are designed to selectively modulate the cellular signals that are aberrant in disease processes caused by the dysregulation of mTORC1 activation to address a wide range of diseases, including neurological and fibrotic disorders, immunometabolism and certain rare diseases. The company’s founding intellectual property is based on groundbreaking discoveries related to the mTORC1 pathway and nutrient signaling mechanisms by Dr. David Sabatini at The Whitehead Institute for Biomedical Research. The company is backed by leading financial and corporate investors, including Polaris Partners, Atlas Venture, Johnson & Johnson Innovation – JJDC, Inc., SR One, Ltd., Brace Pharma Capital, Remeditex Ventures and Sanofi Ventures. For more information, please visit www.navitorpharma.com.
- Duman, RS and Aghajanian, GK. Science. 2012 October 5; 338(6103): 68–72.
- Scheung, L, et al., Frontiers in Neuroscience. 2015 July 21; 9 (249).