Navitor Pharmaceuticals Announces Peer-Reviewed Publication in Journal of Clinical Investigation Highlighting Rapid Antidepressant Effects of NV-5138

Single Oral Dose Resulted in Rapid and Long-Lasting Pharmacological
Efficacy Across Multiple Models of Depressive Behavior

CAMBRIDGE, Mass.–(BUSINESS WIRE)–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, Navitor’s 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.

About NV-5138

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).
Navitor’s strong intellectual property portfolio includes issued
composition of matter patent protection for NV-5138 and related
compounds.

About mTORC1

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

About Navitor

Navitor Pharmaceuticals, Inc. is the leader in the development of
mTORC1-targeted therapeutics designed to help patients live longer and
healthier lives. The Company’s 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. Navitor’s 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 Company’s NΛValog
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

Contacts

Media
David Rosen
Argot
Partners
david.rosen@argotpartners.com
(212)
600-1902

Investors
Laura Perry/Ryan Baker
Argot
Partners
Laura@argotpartners.com
or ryan@argotpartners.com
(212)
600-1902