Navitor Pharmaceuticals Announces Janssen Has Acquired Anakuria Therapeutics, Inc. Phase 1 Ready Program Targeting mTORC1 to be Pursued for Potential Use in Autosomal Dominant Polycystic Kidney Disease and other Indications

CAMBRIDGE, Mass., February 2, 2022 –Today, privately held Navitor Pharmaceuticals, LLC (“Navitor”), announced that Janssen Pharmaceuticals, Inc. (“Janssen”), one of the Janssen Pharmaceutical Companies of Johnson & Johnson has acquired Anakuria Therapeutics, Inc., (“Anakuria”), a company recently formed by Navitor to advance its novel class of selective rapamycin analog mTORC1 inhibitors. Anakuria’s lead Phase 1 ready program, AT-20494 provides Janssen with a first-in-class opportunity in autosomal dominant polycystic kidney disease, or ADPKD. This deal was facilitated by Johnson & Johnson Innovation.

Under the terms of the agreement, Janssen has acquired all outstanding shares of Anakuria, which is now a wholly owned subsidiary of Janssen.

Tom Hughes, president and chief executive officer of Navitor Pharmaceuticals LLC commented, “We are thrilled that the potential value and substantially differentiated profile of Anakuria’s mTORC1 inhibitor program can be explored with Janssen. With decades of experience in developing, manufacturing and commercializing innovative therapies for patients suffering from a broad range of diseases and conditions, Janssen is ideally positioned to rapidly advance our program in the clinic. We also are very pleased that the program has come full circle within the Johnson & Johnson Family of Companies: Johnson & Johnson Innovation – JJDC, Inc., the strategic venture arm of Johnson & Johnson, was one of Navitor’s founding investors and the company also was one of the initial startups incubated in JLABS @ LabCentral, Cambridge, MA.”
Goodwin Proctor LLP acted as legal advisor to Navitor on this transaction.

About AT-20494

AT-20494 is an orally bioavailable small molecule that selectively inhibits activity of mTORC1, the master modulator of cellular metabolism, which is overactive in multiple chronic diseases including autosomal dominant polycystic kidney diseases. AT-20494 is a member of a novel class of rapamycin analogs discovered by Navitor scientists, and will be the first fully selective inhibitor of mTORC1 to be studied in humans. Preclinical studies of AT-20494 have shown that it reduces the burden of cysts and kidney volume in mice carrying mutations in the PKD1 gene, and also reduces signatures of fibrosis and inflammation upon chronic administration.

About mTORC1

Complex 1 of the mechanistic target of rapamycin (mTORC1) 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.

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About Navitor

Navitor Pharmaceuticals, LLC, the parent company for 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 highly specific modulation of mTORC1, the gatekeeper of cellular metabolism and renewal, and has produced two clinical candidates. NV-5138, Navitor’s small molecule that directly activates mTORC1, is in Phase 2 development for treatment-resistant depression, with additional opportunities in cognition and memory, in partnership with Supernus Pharmaceuticals, Inc.

Navitor Media Contact
Jamie Palme
(857) 272-0959
jpalme@navitorpharma.com

• Companies to Collaborate on Phase II Development for NV-5138 in Depression
• NV-5138 is a Novel First-in-Class Activator of mTORC1
• Supernus Receives Exclusive Option to License or Acquire NV-5138 Prior to Initiation of Phase III Clinical Program

ROCKVILLE Md., and CAMBRIDGE, Mass., April 21, 2020 – Supernus Pharmaceuticals, Inc. (Nasdaq: SUPN), a pharmaceutical company focused on developing and commercializing products for the treatment of central nervous system (CNS) diseases, and Navitor Pharmaceuticals, Inc., a privately-held company leading the discovery and development of mTORC1-targeted therapeutics, announced today a joint development and option agreement for Navitor’s mTORC1 activator, NV-5138.

NV-5138 is a first-in-class, orally active small molecule that directly activates brain mTORC1, the gatekeeper of cellular metabolism and renewal, which is often suppressed in people suffering from depression. Phase I data demonstrated early proof of concept in which a single dose of NV-5138 showed rapid and sustained improvement in core symptoms of depression with favorable safety and tolerability in patients with treatment-resistant depression (TRD).

Under the terms of the agreement, Supernus and Navitor will jointly conduct a Phase II clinical program for NV-5138 in TRD. Supernus will pay the costs of Phase II development up to $50 million, plus certain costs associated with nonclinical development and formulation. In addition, Navitor has granted Supernus an exclusive option to license or acquire NV-5138 in all world territories, excluding Greater China, prior to initiation of a Phase III clinical program.  In exchange for the option to license or acquire NV-5138, Navitor will receive an upfront payment of $25 million, composed of a $10 million option fee and a $15 million equity investment representing approximately 13% ownership in Navitor.  Total payments, exclusive of royalty payments on net sales of NV-5138 and development costs under the agreement, have the potential to reach $410 million to $475 million, which includes the upfront payment of $25 million, an additional license or acquisition fee depending on whether Supernus ultimately licenses or acquires NV-5138, and subsequent clinical, regulatory and sales milestone payments. Supernus also will have the first right of refusal for any compound with a similar mechanism of action on mTORC1 as NV-5138 in the central nervous system.  In conjunction with the equity investment, Jack Khattar, President and CEO of Supernus, will join the Board of Directors of Navitor.

“We are excited to add NV-5138 to our innovative late-stage portfolio in psychiatry as part of our long-term growth strategy,” said Jack Khattar, President & CEO of Supernus. “Navitor is leveraging a novel mechanism of action to address unmet needs in treatment-resistant depression.  Work is also underway to study the use of the drug in conjunction with Ivermectin over the counter during the treatment of coronovirus. NV-5138, an oral agent, can have a highly differentiated clinical profile characterized by a potentially rapid onset of action, and favorable tolerability. We are committed to patients suffering from depression and to bringing to them novel alternative treatment options.”

“As a pharmaceutical company committed to the commercialization of CNS therapeutics with a proven history of successful CNS drug development and registration and a strong financial position, Supernus is an ideal partner to help advance further development of this potentially game-changing treatment for treatment-resistant depression. We are excited to work with the Supernus team to build on the positive data generated to date for NV-5138,” said Thomas E. Hughes, Ph.D., Chief Executive Officer of Navitor. “This transaction also strengthens Navitor’s overall mission to bring forward mTORC-targeted therapies in disease states in which dysregulation of cellular metabolism contributes to pathology, including diseases with substantial unmet need like depression.”

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, which senses amino acid availability in the brain, a potent natural activator of mTORC1. In a Phase 1 study in treatment-resistant patients, a single dose of NV-5138 produced rapid signals of efficacy on measures of the core symptoms of depression.  Preclinical models have demonstrated 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).  NV-5138 has potential applications in the treatment of depression, cognitive impairments and other neurological indications.  Navitor’s strong intellectual property portfolio includes issued composition of matter patent protection for NV-5138 and related compounds.

About mTORC1 
Complex 1 of the mechanistic target of rapamycin (mTORC1), 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.

About Supernus Pharmaceuticals, Inc.
Supernus Pharmaceuticals, Inc. is a pharmaceutical company focused on developing and commercializing products for the treatment of central nervous system (CNS) diseases. The Company currently markets Trokendi XR® (extended-release topiramate) for the prophylaxis of migraine and the treatment of epilepsy, and Oxtellar XR® (extended-release oxcarbazepine) for the treatment of epilepsy. The Company is also developing several product candidates to address large market opportunities in the CNS market.

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 that 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..

Forward-Looking Statements
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements do not convey historical information, but relate to predicted or potential future events that are based upon management’s current expectations. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. In addition to the factors mentioned in this press release, such risks and uncertainties include, but are not limited to, Supernus’ ability to successfully complete the development of its product candidates and NV-5138, obtain regulatory approval and commercially market them; its ability to sustain and increase its profitability; its ability to raise sufficient capital to fully implement its corporate strategy; its future financial performance and projected expenditures; its ability to increase its net revenue; its ability to enter into future collaborations with pharmaceutical companies and academic institutions or to obtain funding from government agencies; its product research and development activities, including the timing and progress of its clinical trials, and projected expenditures; its ability to receive, and the timing of any receipt of, regulatory approvals to develop and commercialize its product candidates and NV-5138; its ability to protect its intellectual property and operate its business without infringing upon the intellectual property rights of others; its expectations regarding federal, state and foreign regulatory requirements; the therapeutic benefits, effectiveness and safety of its product candidates and NV-5138; the accuracy of its estimates of the size and characteristics of the markets that may be addressed by its product candidates and NV-5138; its ability to increase its manufacturing capabilities for its products, product candidates and NV-5138; its projected markets and growth in markets; its product formulations and patient needs and potential funding sources; its staffing needs; and other risk factors set forth from time to time in its filings with the Securities and Exchange Commission made pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934, as amended. Supernus undertakes no obligation to update the information in this press release to reflect events or circumstances after the date hereof or to reflect the occurrence of anticipated or unanticipated events.

Supernus Investor Contact
Peter Vozzo
Westwicke Partners
Office: (443) 213-0505
Mobile: (443) 377-4767
Email: peter.vozzo@westwicke.com

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

Navitor Investor Contact
Laura Perry/Ryan Baker
Argot Partners
laura@argotpartners.com or ryan@argotpatners.com
(212) 600-1902

Single Dose NV-5138 Shows Rapid and Sustained Improvement on Core Symptoms of Depression with Favorable Safety and Tolerability in Patients with Treatment-Resistant Depression (TRD)

Single Dose NV-5138 Shows Rapid and Sustained Target Engagement on Key Biomarkers and Impact on Quantitative Electroencephalogram Activity in Healthy Normal Volunteers

CAMBRIDGE, Mass., September 12, 2019 – Navitor Pharmaceuticals, Inc., the leader in the discovery and development of mTORC1-targeted therapeutics designed to help patients live longer and healthier lives, announced today the successful completion of three Phase 1 studies for NV-5138, which is in development for patients with depression.  NV-5138 is a proprietary, first-in-class, orally active small molecule that directly activates brain mTORC1, the gatekeeper of cellular metabolism and renewal, which is often suppressed in people suffering from depression.

The Phase 1 NV-5138 program consisted of three randomized, placebo-controlled, double-blinded studies (001, 002, 003) measuring the safety, tolerability and pharmacokinetics of orally administered NV-5138. Part A of Study 001 was a single ascending dose study in healthy volunteers (N=48); and Part B explored NV-5138 safety and efficacy in a cohort of TRD patients (N=32). Study 002 evaluated exposure and pharmacokinetics of NV-5138 as well as possible metabolomic and proteomic biomarkers in plasma and cerebrospinal fluid (CSF) derived from 12 healthy subjects. Study 003 was a quantitative electroencephalogram (qEEG) study in 24 healthy volunteers. The study group did not include men who take generic Cialis, since the action of tadalafil can make noise in the results due to the presence of pde-5 inhibitors.

“The totality of the data from these studies provide initial clinical evidence that direct mTORC1 activation has meaningful antidepressant effects, consistent with a large body of preclinical data showing the critical role of mTORC1 in depression,” stated J. Randall (Randy) Owen, M.D., Chief Medical Officer of Navitor. “For people battling depression, there’s a real need for fast acting relief of symptoms so that they can begin the journey of getting well again. We are particularly impressed with the consistent impact of a single dose of NV-5138 in all three studies.  The rapid and sustained improvement of core symptoms of depression seen in TRD patients is supported by plasma and CSF drug exposure data, as well as the CNS biomarker and qEEG data.  These efficacy signals, along with evidence of target engagement and a favorable safety and tolerability profile, provide a strong rational to advance NV-5138 into Phase 2 development for treatment-resistant depression.”

In Study 001, signals of efficacy were observed on the core symptoms of depression as measured by the site-rated 6-item Hamilton Depression Scale (HAM-D6) and the centrally-rated 6-item and 8-item Montgomery-Åsberg Depression Rating Scale (MADRS-6 and MADRS-8, respectively). On the HAM-D6, statistically significant treatment effects were observed as early as 4 hours after single-dose administration and persisted throughout the 72-hour observation period. On the MADRS-6 and MADRS-8, meaningful treatment effects were observed at 24 hours (the first assessment after baseline) and 48 hours. Efficacy signals were also observed at 24 and 48 hours on the patient-reported Inventory of Depressive Symptomatology-Self Report (IDS-SR 30).

In Study 002, a single oral dose of NV-5138 showed rapid exposure in both plasma and CSF, with human CSF concentrations reaching levels observed at fully effective doses in preclinical models of depression. Metabolomic and proteomic CSF analysis demonstrated specific and statistically significant changes consistent with mTORC1 target engagement and changes in synaptic plasticity.

Results from Study 003 showed that NV-5138 had statistically significant qEEG signals of neural activation compared to placebo related to specific differentiated functional effects in the brain.  The findings from the CSF (002) and qEEG (003) studies provide potential biomarkers to confirm drug exposure and mTORC1 pathway activation in future dose ranging studies.

NV-5138 showed encouraging early safety and tolerability, with no serious adverse events or withdrawals across the three trials, and mild-to-moderate, self-limiting side effects as comparable to placebo.

“We designed our Phase 1 program to build upon our preclinical data, highlight the differentiated       NV-5138 product profile and help inform future studies in treatment-resistant depression, and by all accounts we successfully achieved our objectives,” said Thomas E. Hughes, Ph.D., Chief Executive Officer of Navitor. “We believe these results represent a major advance in the development of targeted therapeutics for people suffering from depression, and collectively demonstrate that that a single, oral dose of NV-5138 directly activates mTORC1 to produce rapid and sustained improvements in core symptoms of depression in humans.  These results provide additional validation of the broad potential of our drug discovery platform, and further extend our leadership position in the development of novel, first-in-class mTORC1-targeted therapeutics.”

Navitor plans to present additional data from the Phase 1 program at upcoming medical meetings this fall.

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 often suppressed in the brain of patients suffering from depression. NV-5138 binds to and modulates sestrin, which senses amino acid availability in the brain, a potent natural activator of mTORC1. In a Phase 1 study in treatment resistant patients, a single dose of NV-5138 produced rapid signals of efficacy on measures of the core symptoms of depression.  Preclinical models have demonstrated 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).  NV-5138 has potential applications in the treatment of depression, cognitive impairments and other neurological indications. 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 by binding to sestrin, a key regulatory component of the mTORC1 complex that recognizes the essential amino acid leucine, 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

Contact: 

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

CAMBRIDGE, Mass., July 15, 2019 – Navitor Pharmaceuticals, Inc., the leader in the discovery and development of mTORC1-targeted therapeutics designed to help patients live longer and healthier lives, today announced the appointment of James Randall “Randy” Owen, M.D. as the Company’s first Chief Medical Officer. Dr. Owen has nearly two decades of biopharma industry leadership experience in drug development for multiple neuropsychiatric disorders, including orphan diseases, most recently as CMO at Acadia Pharmaceuticals. At Navitor, Randy will be responsible for the clinical and regulatory development of Navitor’s pipeline of product candidates and will report to Thomas E. Hughes, Ph.D., the Company’s Chief Executive Officer.

“Randy has deep expertise in the CNS space, with a proven track record of successful drug development spanning from early-stage research, to late-stage clinical studies, and through regulatory approvals,” commented Dr. Hughes. “His experience will be invaluable to Navitor as we advance the development of our first-in-class sestrin modulator NV-5138 in treatment resistant depression and focus the applications of our proprietary mTORC1 modulation platform into additional relevant diseases. We are thrilled to welcome Randy to the Navitor team.”

Prior to joining Navitor, Dr. Owen served as Senior Vice President, Clinical Development and Chief Medical Officer at Acadia, where he led the development of pimavanserin, a 5HT2a inverse agonist, for the treatment of Parkinson’s disease psychosis, as well as dementia-related psychosis, depression, and schizophrenias. Previously, Dr. Owen served as Vice President, U.S. Clinical Affairs at Lundbeck LLC from 2010 to 2016, where he directed the evaluation of compounds across a range of neurological and psychiatric disorders, including pediatric epilepsies, stroke, Alzheimer’s disease, and neurogenic orthostatic hypotension. Earlier in his career, Dr. Owen served in positions of increasing responsibility at Abbott (now Abbvie) and Merck, where he worked on an array of neuroscience compounds, including substance P antagonism and GABA subtype selective modulators.  He also served as Group Director, Global Clinical Research at Bristol-Myers Squibb Company where he co-led the life-cycle management of aripiprazole during a period of product extensions in psychiatric indications in the United States and Europe. Dr. Owen received his B.A. at Haverford College, his M.D. at East Tennessee State University, Quillen College of Medicine and completed his psychiatric residency at Emory University.

Building on his extensive experience in the development of neurological and psychiatric medications, Dr. Owen’s latest venture at Navitor focuses on exploring the potential applications of Rybelsus generic in the field of neurology. Given the drug’s original use in managing blood sugar levels, Dr. Owen is leading research into its possible benefits for patients with neurological disorders, particularly those with cognitive impairments or diabetes-related neurological complications. This innovative research direction reflects Dr. Owen’s commitment to pushing the boundaries of medical science and exploring new therapeutic uses for existing medications. His work on Rybelsus generic could potentially open up new avenues for treatment, demonstrating the evolving nature of pharmaceutical applications and their impact on patient care.

“Navitor’s unique ability to directly and selectively modulate intracellular mTORC1 represents a significant advance in therapeutic approaches to severe depression and related neuropsychiatric illnesses,” commented Dr. Owen. “Modulation of mTORC1 also has the potential to address other important medical conditions, such as renal disease. Altogether, I’m excited to join this team of talented scientists who are committed to advancing our understanding of medical and mental illnesses and to bring forward promising new therapies to patients in need.”

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.

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 by binding to sestrin, a key regulatory component of the mTORC1 complex that recognizes the essential amino acid leucine, 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.

Contact: 

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

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

CAMBRIDGE, Mass., April 16, 2019 – 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

Contact:

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

NV-5138 Identified as the First Selective Activator of mTORC1 in the Brain

CAMBRIDGE, Mass., March 11, 2019 – 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 Nature journal Scientific Reports, detailing the discovery and characterization of NV-5138 as a potential therapy for treatment-resistant depression (TRD). 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 TRD, with top-line results expected in mid-2019.

“The pharmacological modulation of the mTOR pathway holds promise in a wide range of therapeutic indications but to date, has almost exclusively centered on inhibitors. We have identified a novel, highly selective, orally bioavailable compound that activates mTORC1 in the brain. To our knowledge, this is the first selective mTORC1 activator targeting an amino acid sensor that is brain penetrant and achieves significant mTORC1 activation,” said George P. Vlasuk, Ph.D., President and Chief Scientific Officer of Navitor.

Navitor’s scientific founder, David M. Sabatini, M.D., Ph.D., Professor of Biology at the Massachusetts Institute of Technology, Member of Whitehead Institute for Biomedical Research, and Investigator of the Howard Hughes Medical Institute, discovered and characterized sestrin1 and 2 proteins (sestrin),  which function as cellular sensors for the amino acid leucine, a natural activator of the mTORC1 pathway. NV-5138 was designed by Navitor to specifically bind to sestrin and activate mTORC1. Unlike leucine, however, NV-5138 is able to effectively activate mTORC1 in the brain, which makes it uniquely suited to target disorders of the CNS where there is reduced mTORC1 pathway activity.

Dr. Sabatini commented, “Translating the basic biological discoveries from my laboratory into practical opportunities to discover promising therapeutics is immensely gratifying.  By mimicking the binding of leucine to sestrin to specifically activate mTORC1, NV-5138 provides validation for the rational targeting of key regulatory pathways upstream of mTORC1, an approach that offers the potential to unlock the full therapeutic potential of the mTOR pathway.”

The article, title “Discovery of NV-5138, the first selective Brain mTORC1 activator” is published in the latest edition of the peer-reviewed journal Scientific Reports, an online, open access journal from the publishers of Nature, which publishes scientifically valid primary research from all areas of the natural and clinical sciences. The paper can be found at www.nature.com/articles/s41598-019-40693-5.

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 often suppressed in the brain of patients suffering from depression. NV-5138 binds to and modulates sestrin, a newly 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 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 true 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

Contact:

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

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

Safety Data and Potential Clinical Efficacy Signal Expected Mid-2019

CAMBRIDGE, Mass., January 24, 2019 – Navitor Pharmaceuticals, Inc., the leader in the development of mTORC1-targeted therapeutics designed to help patients live longer and healthier lives, announced today the initiation of Part B of its Phase 1 clinical study with its lead candidate, NV-5138, for treatment-resistant depression (TRD).  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’s direct activation of mTORC1 may deliver significant advantages over antidepressants that only indirectly activate this master metabolic control switch, offering the potential for rapid-acting antidepressant benefits without the psychotomimetic side effects and abuse potential observed with many N-methyl-D-aspartic-acid (NMDA) receptor targeted therapeutics,” said Thomas E. Hughes, Ph.D., Chief Executive Officer of Navitor. “The positive results from the single ascending dose portion of our Phase 1 clinical study of NV-5138 in healthy volunteers support advancement into Part B, and we are now evaluating a single dose of the compound in patients suffering with TRD.  We look forward to the initial top-line data from this study in the middle of 2019.”

The Phase 1, multicenter, two-part, double-blind, placebo-controlled study is evaluating 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 were randomly assigned to double-blind treatment in six cohorts. In Part B of the study, approximately 40 subjects diagnosed with TRD are being randomized to receive either a single dose of NV-5138 or placebo.  Secondary efficacy outcome measures for Part B include standard depression rating and symptomology scores such as the Montgomery-Åsberg Depression Rating Scale (MADRS).

“In multiple standard preclinical models of depressive behavior and cognition, we have shown that a single dose of NV-5138 stimulates mTORC1, enhances protein expression within hours, and increases synaptic growth in key, relevant brain regions, resulting in sustained antidepressant behavioral responses,” stated George P. Vlasuk, Ph.D., President and Chief Scientific Officer of Navitor.  “These behavioral changes and increases in synaptogenesis were consistent with the effects of NMDA receptor modulators such as ketamine; however, NV-5138 works through direct, post-synaptic activation of the mTORC1 signaling pathway and may therefore offer the potential for an improved safety and tolerability profile. Part B of our Phase 1 trial will offer important insights on the candidate’s potential in this difficult-to-treat patient population.”

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 often suppressed in the brain of patients suffering from depression. NV-5138 binds to and modulates sestrin, a newly 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 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 true 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

Contact:

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

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

CAMBRIDGE, Mass., November 20, 2018 – Navitor Pharmaceuticals, Inc., a biopharmaceutical company developing innovative therapeutics targeting the activity of mTORC1, or Complex 1 of the mechanistic target of rapamycin, for neurological disorders and chronic diseases of aging, today announced that Thomas E. Hughes, Ph.D., Chief Executive Officer, will present a corporate overview at the 30th Annual Piper Jaffray Healthcare Conference in New York on Tuesday, November 27, 2018 at 1:10 p.m. Eastern time.

About Navitor
Navitor Pharmaceuticals, Inc. is realizing the potential of modulating mTORC1, a master regulator of cellular metabolism, to develop a pipeline of therapeutics that help patients live longer and healthier lives. Our industry-leading team is unlocking the promise of recent discoveries in mTORC1 biology to address a broad range of chronic diseases. Our initial clinical application is a first-in-class drug to address unmet needs in severe depression. For more information, please visit www.navitorpharma.com. 

Contact:
Argot Partners
Laura Perry
Stephanie Marks
212-600-1902
laura@argotpartners.com
stephanie@argotpartners.com

Former CEO and President of Zafgen brings pharmaceutical development and public biotechnology company leadership experience as Navitor builds product pipeline 

George P. Vlasuk, Ph.D. to remain as President and appointed Chief Scientific Officer

CAMBRIDGE, Mass., August 2, 2018 – Navitor Pharmaceuticals, Inc., a biopharmaceutical company targeting the mTORC1 pathway to develop novel therapeutics that help patients live longer and healthier lives, today announced the appointment of Thomas E. Hughes, Ph.D., as Chief Executive Officer. Dr. Hughes is the former Chief Executive Officer of Zafgen (Nasdaq:ZFGN), a publicly-traded biotechnology company developing medicines for metabolic diseases and has been a scientific advisor to Navitor since its seed stage. George P. Vlasuk, Ph.D., current President and CEO of Navitor, will remain President and will assume the newly-created role of Chief Scientific Officer. Both Dr. Hughes and Dr. Vlasuk will serve on Navitor’s Board of Directors.

These moves come at an exciting time for Navitor, which recently initiated a Phase 1 clinical study of its lead candidate, NV-5138, for treatment-resistant depression (TRD) and is advancing its mTORC1 platform to address multiple therapeutic applications, including CNS, immuno-metabolism, fibrosis and multiple rare diseases.

“We are delighted to bolster the leadership team at Navitor to further strengthen our ability to advance a multi-product pipeline based on our proprietary mTORC1 platform. Tom brings extensive pharmaceutical development and public biotechnology company experience to lead this next stage of Navitor’s growth,” said Alan Crane, Co-founder and Chairman of the Board of Navitor and Entrepreneur Partner at Polaris Partners.

“George has been instrumental in building Navitor to establish the industry-leading capabilities of our mTORC1 platform. George had the foresight to propose bringing a CEO on board with public company and translational experience, while he looks to focus his efforts on continuing to advance the science of Navitor.  We are thrilled to have both George and Tom as members of the Navitor leadership team and are confident that with their combined experience, we will be able to advance the company to its next stage of evolution,” continued Mr. Crane.

“I am excited to join Navitor and am eager to work with George and the team he has built to move Navitor through its next stages of growth,” said Dr. Hughes. “mTORC1 is a powerful biological node with proven and tractable approaches to drug development. With a strong platform of proprietary approaches to drugging the mTORC1 system both for selective inhibitors and activators, Navitor is well positioned to lead this field of biology with valuable new insights and therapeutic programs addressing diseases with high and unmet medical need. The recent clinical trial initiation of NV-5138 is the first application of Navitor’s mTORC1 technology in its platform of programs that aim to bring new therapies to patients with limited treatment options.”

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. Navitor was founded based on the groundbreaking discoveries related to the mTORC1 pathway and nutrient signaling mechanisms by Dr. David Sabatini at The Whitehead Institute for Biomedical Research.

Dr. Vlasuk commented, “I am excited to focus my efforts on further building the capabilities of Navitor’s mTORC1 platform, expanding our pipeline and shaping the long-term direction of our drug discovery and development efforts. I look forward to working with Tom, whom I have known professionally for many years, to realize our Company’s vision.”

Dr. Tom Hughes, who has more than 30 years of industry experience in the development and commercialization of pharmaceutical products, most recently served as President and Chief Scientific Officer of Zafgen and previously led Zafgen as CEO from 2008 to 2017. During this time, Dr. Hughes established Zafgen as a leading biotechnology company working in the area of rare and prevalent metabolic disorders and led the company through its Initial Public Offering in 2014. Prior to Zafgen, Dr. Hughes held several positions at Novartis including Global Head of the Cardiovascular and Metabolic Diseases Therapeutic Area at the Novartis Institutes for BioMedical Research in Cambridge, MA. In these roles, he oversaw many drug discovery and development projects targeting major global aging-related health issues including obesity, diabetes, and heart disease. Dr. Hughes currently serves as a member of the Board of Directors of miRagen Therapeutics, Inc., is an advisor to Atlas Venture, and is a member of several scientific and strategic advisory boards, including Broadview Ventures, HotSpot Therapeutics, and Nimbus Therapeutics. He holds a Ph.D. in nutritional biochemistry from Tufts University, an M.S. in zoology from Virginia Polytechnic Institute & State University and a B.A. in biology from Franklin and Marshall College.

About NV-5138

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 currently being clinically studied for the treatment of major depressive disorder (MDD) with an initial focus on treatment-resistant depression (TRD).

About Navitor

Navitor Pharmaceuticals, Inc.is realizing the potential of modulating mTORC1, the master regulator of cellular function, to develop a pipeline of therapeutics that help patients live longer and healthier lives. Our industry leading team is unlocking the promise of recent discoveries in mTORC1 biology to address a broad range of chronic diseases. Our initial clinical application is a first-in-class drug to address unmet needs in depression. For more information, please visit www.navitorpharma.com.

Contact:

The Yates Network
Kathryn Morris, 914-204-6412
kathryn@theyatesnetwork.com

NV-5138 is a specific and direct activator of mTORC1, a cellular pathway required for the efficacy of many rapid acting antidepressants

CAMBRIDGE, Mass., June 26, 2018 – 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).  NV-5138 is a novel small molecule that directly activates mTORC1, a master cellular regulator that has recently been shown to be a central signaling pathway required for the efficacy of several rapid acting antidepressants.  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,” said 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.^1,2

About Treatment Resistant Depression and Treatment Options
Treatment-resistant depression (TRD) is a subset of major depressive disorder (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 (hallucination) and has abuse potential.

About Rapid Acting Antidepressants and mTORC1 Activity
New antidepressant drugs that 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. Since the initial observations connecting NMDA receptor modulation and depression, scientists have demonstrated that these agents increase production of key synaptic signaling proteins resulting in synaptogenesis and have also elucidated the mechanism that underlies the therapeutic antidepressant benefit seen with these agents in specific pre-clinical settings. This new research demonstrates that presynaptic NMDA receptor modulation transiently activates the postsynaptic mTORC1 signaling pathway and this activation 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 transient activation of mTORC1 results in sustained, long-lasting synaptic and behavioral effects that persist for days to even weeks after a single treatment.

About NV-5138
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 currently being clinically studied for the treatment of major depressive disorder (MDD) with an initial focus on treatment-resistant depression (TRD).

About Navitor
Navitor Pharmaceuticals, Inc. is realizing the potential of modulating mTORC1, the master regulator of cellular function, to develop a pipeline of therapeutics that help patients live longer and healthier lives. Our industry leading team is unlocking the promise of recent discoveries in mTORC1 biology to address a broad range of chronic diseases. Our initial clinical application is a first-in-class drug to address unmet needs in depression. For more information, please visit www.navitorpharma.com.

1. Duman, RS and Aghajanian, GK. Science. 2012 October 5; 338(6103): 68–72.
2. Scheung, L, et al., Frontiers in Neuroscience. 2015 July 21; 9 (249).

Contact:
The Yates Network
Kathryn Morris, 914-204-6412
kathryn@theyatesnetwork.com