Navitor’s Three Phase 1 Studies for NV-5138 Show Antidepressant Effects and Biomarker Impact, Supporting Further Development of Direct Activator of mTORC1 in 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 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 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.

Zanos, P. et al., CNS Drugs. 2018; 32(3): 197-227

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