A new option for depression enters Phase 1

Navitor Pharmaceuticals initiates a clinical study of NV-5138, a novel oral small molecule for treatment-resistant depression

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CAMBRIDGE, Mass.—Navitor Pharmaceuticals, Inc., a biopharmaceutical company targeting the mTORC1 pathway to develop novel therapeutics that help patients live longer and healthier lives, announced today the initiation of a Phase 1 clinical study with its lead pipeline candidate, NV-5138, for treatment-resistant depression (TRD).

TRD is a subset of MDD that refers to depressive episodes that are not adequately controlled by standard antidepressant therapy. Several studies including a postmortem analysis of healthy and severely depressed patients as well as multiple pre-clinical settings have suggested an association between the activity of mTORC1 pathway signaling and depression. Standard antidepressant therapies, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are only modestly effective, and have a very slow onset typically taking 6-8 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 modulation can cause significant side effects including dissociation and hallucination, and has abuse potential.

NV-5138 is an orally bioavailable small molecule that is designed to directly and transiently
activate mTORC1 activity by binding to and modulating a newly discovered cellular sensor protein for the amino acid leucine, which is a potent natural activator of mTORC1. Unlike leucine, oral administration of NV-5138 results in significant mTORC1 pathway activation in the brain since it is not broken down or incorporated into new proteins. These properties make NV-5138 a unique agent with which to evaluate the role of mTORC1 in brain disorders, such as depression, where mTORC1 activity is often suppressed.
Results from preclinical models demonstrate that NV-5138 produces rapid upregulation of key synaptic proteins, synaptogenesis and sustained antidepressant behavioral responses via the transient and direct activation of the mTORC1 signaling pathway. Since NV-5138 does not directly modulate the NMDA receptor pathway, it may not have the side effects and abuse potential observed with several NMDA receptor therapeutics currently in development. NV-5138 is initially being evaluated in TRD, but may offer future potential for the treatment in the broader disease category of major depressive disorder (MDD).
“We are enthusiastic about initiating clinical development with NV-5138 for major depressive disorder, as we believe this novel activator of mTORC1 has the potential to offer a unique approach to meeting many of the unmet needs of this serious and chronic disease. Millions of patients with depression do not adequately respond to standard pharmacological therapies which can take weeks or months before patients experience their effects, if at all,” said George P. Vlasuk, PhD, President and Chief Executive Officer of Navitor. “We see the development of NV-5138 in MDD/TRD as a pioneering advance toward realizing the therapeutic potential of modulating the mTORC1 signaling pathway to treat a wide range of chronic human diseases.”
The Phase 1, multicenter, two-part, double-blind, placebo-controlled study will evaluate the safety, tolerability and pharmacokinetics of NV-5138 in up to 88 subjects, including healthy volunteers and patients diagnosed with TRD. In Part A, the single-ascending-dose portion of the study, up to 48 healthy volunteers will be randomly assigned to double-blind treatment in six dosage-level cohorts. Within each cohort, six subjects will be randomized to receive NV-5138 and two subjects will be randomized to receive placebo. In Part B of the study, approximately 40 subjects diagnosed with TRD will be randomly assigned to double-blind treatment at a single dosage level that will be established based on data from Part A of the study. Other prespecified outcome measures to be evaluated in Part B include standard depression rating and symptomology scores such as the Montgomery-Åsberg Depression Rating Scale (MADRS).
“Initiation of this clinical study is supported by preclinical studies demonstrating the potential of NV-5138 as an oral treatment for depression through activation of mTORC1, a cellular pathway that appears to underlie the beneficial effects of several in a new class of rapidly acting antidepressants,” noted Maurizio 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.
Previously, Navitor has presented preclinical results on the efficacy of NV-5138 in multiple models of depression-like behavior, which demonstrated that NV-5138 produced behavioral responses and concomitant increases in new synapses (synaptogenesis) consistent with a rapid-acting antidepressant through transient, direct activation of the mTORC1 signaling pathway in the brain. Navitor leveraged multiple preclinical observations that have shown mTORC1 activation is required for the efficacy of many rapid-acting antidepressant compounds including several 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.

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